Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

Review Article | Open AccessVolume 2019 |Article ID 8201079 | 14 pages | https://doi.org/10.1155/2019/8201079

Academic Editor: Kanhaiya Singh Received 24 Jul 2019 Revised12 Sep 2019 Published14 Nov 2019 Accepted11 Oct 2019

  • Tiziana Tataranni 1 and Claudia Piccoli 1,2
  • 1Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), 85028, Italy
  • 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia 71121, Italy

Abstract

An extensive body of literature describes anticancer property of dichloroacetate (DCA), but its effective clinical administration in cancer therapy is still limited to clinical trials. The occurrence of side effects such as neurotoxicity as well as the suspicion of DCA carcinogenicity still restricts the clinical use of DCA. However, in the last years, the number of reports supporting DCA employment against cancer increased also because of the great interest in targeting metabolism of tumour cells. Dissecting DCA mechanism of action helped to understand the bases of its selective efficacy against cancer cells. A successful coadministration of DCA with conventional chemotherapy, radiotherapy, other drugs, or natural compounds has been tested in several cancer models. New drug delivery systems and multiaction compounds containing DCA and other drugs seem to ameliorate bioavailability and appear more efficient thanks to a synergistic action of multiple agents. The spread of reports supporting the efficiency of DCA in cancer therapy has prompted additional studies that let to find other potential molecular targets of DCA. Interestingly, DCA could significantly affect cancer stem cell fraction and contribute to cancer eradication. Collectively, these findings provide a strong rationale towards novel clinical translational studies of DCA in cancer therapy.

1. Introduction

Cancer is one of the leading causes of death worldwide. Despite the significant progression in diagnostic and therapeutic approaches, its eradication still represents a challenge. Too many factors are responsible for therapy failure or relapse, so there is an urgent need to find new approaches to treat it. Apart from the typical well-known properties featuring malignant cells, including abnormal proliferation, deregulation of apoptosis, and cell cycle [12], cancer cells also display a peculiar metabolic machine that offers a further promising approach for cancer therapy [35]. Our group had already suggested the importance of a metabolic characterization of cancer cells to predict the efficacy of a metabolic treatment [6]. Drugs able to affect cancer metabolism are already under consideration, showing encouraging results in terms of efficacy and tolerability [7]. In the last decade, the small molecule DCA, already used to treat acute and chronic lactic acidosis, inborn errors of mitochondrial metabolism, and diabetes [8], has been largely purposed as an anticancer drug. DCA is a 150 Da water-soluble acid molecule, analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms (Figure 1(a)) [9]. DCA administration in doses ranging from 50 to 200 mg/Kg/die is associated to a decrease of tumour mass volume, proliferation rate, and metastasis dissemination in several preclinical models [10]. Our group had already observed an inverse correlation between DCA ability to kill cancer cells and their mitochondrial respiratory capacity in oral cell carcinomas [11]. Moreover, we recently described DCA ability to affect mitochondrial function and retarding cancer progression in a pancreatic cancer model [12]. To date, consistent data from clinical trials and case reports describing DCA administration in cancer patients are available [1316], but, despite the growing body of literature sustaining the efficacy of DCA against cancer, it is not under clinical use yet. This review is aimed at summarizing the very recent reports suggesting the employment of DCA in cancer therapy, in combination with chemotherapy agents, radiotherapy, and other chemical or natural compounds showing anticancer properties. Moreover, we described data about new purposed pharmacological formulations of DCA able to avoid side effects and ameliorate drug bioavailability and efficacy, further encouraging its possible clinical employment. Finally, we reviewed latest findings suggesting other potential mechanisms of action of DCA, including new data about its aptitude to affect cancer stem cell fraction.

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(b)Figure 1(a) Chemical structure of DCA. (b) Mechanism of action of DCA: PDK: pyruvate dehydrogenase kinase; PDH: pyruvate dehydrogenase. Black dotted lines, biochemical processes inhibited by DCA; Red arrows, metabolic pathways activated by DCA.

2. DCA and Cancer: Mechanism of Action

The potential efficacy of DCA in cancer therapy comes from metabolic properties of cancer cells, typically characterized by increased glycolytic activity and reduced mitochondrial oxidation, regardless of oxygen availability, the well-known Warburg effect [17]. The excessive glycolysis and the resulting lactate overproduction provoke a state of metabolic acidosis in tumour microenvironment [18]. Glycolysis-derived lactate is taken up by surrounding cells to support tumour growth and inhibits apoptotic cell death mechanisms [1920]. Several enzymes involved in glycolysis regulate apoptosis, and their overexpression in cancer cells contributes to apoptosis suppression [21]. In this setting, salts of DCA selectively target cancer cells shifting their metabolism from glycolysis to oxidative phosphorylation by inhibition of pyruvate dehydrogenase kinase (PDK), the inhibitor of pyruvate dehydrogenase (PDH) [10]. PDH activation fosters mitochondrial oxidation of pyruvate and disrupts the metabolic advantage of cancer cells. Mitochondrial DNA mutations, often occurring in tumorigenesis and resulting in respiratory chain dysfunction [2223], make malignant cells unable to sustain cellular energy demand. Furthermore, reducing lactate production, DCA counteracts the acidosis state of tumour microenvironment, contributing to the inhibition of tumour growth and dissemination [24]. The delivery of pyruvate into mitochondria causes organelles remodelling resulting in an increased efflux of cytochrome c and other apoptotic-inducing factors and upregulation of ROS levels with a consequent reduction of cancer cell viability [9] (Figure 1(b)).

3. Side Effects and Limitations to DCA Employment

Clinical employment of DCA is available in both oral and parenteral formulations, and doses range from 10 to 50 mg/Kg/die [25]. No evidence of severe hematologic, hepatic, renal, or cardiac toxicity confirms DCA safety [26]. Common gastrointestinal side effects often occur in a percentage of patients treated with DCA [15]. The best-known limitation to DCA administration, observed both in preclinical and in clinical studies, is peripheral neuropathy [27]. The selectivity of DCA-induced damage for the nervous system may be due to the lack of well-equipped machinery able to handle a more sustained oxidative phosphorylation in cells producing ATP mostly via glycolysis [28]. The resulting mitochondrial overload compromises the antioxidant systems’ efficiency, unable to face the excessive amount of ROS. In this setting, the contemporary administration of antioxidants should represent a further strategy to minimize DCA-induced neuropathy [27]. The expression and the activity of glutathione transferase zeta1 (GSTZ1), the first enzyme responsible for DCA clearance, may influence the entity of damage. Nonsynonymous functional single-nucleotide polymorphisms (SNPs) in human GSTZ1 gene give rise to different haplotypes that are responsible for a different DCA kinetic and dynamics. A clear association between GSTZ1 haplotype and DCA clearance has been demonstrated. On this basis, a personalized DCA dosage, not only based on body weight, may minimize or prevent adverse effects in patients chronically treated with this drug [29]. The occurrence of neuropathy is associated to DCA chronic oral administration and is a reversible effect, limited to the time of treatment [30]. The intravenous route reduces, therefore, the potential for neurotoxicity and let the achievement of higher drug concentrations bypass the digestive system [13].

Since DCA is among water disinfection by-products found in low concentrations in drinking water, its potential carcinogenicity is under evaluation. Studies performed in mouse models associate DCA early-life exposure to an increased incidence of hepatocellular tumours [31]. It is conceivable that persistent changes in cell metabolism induced by DCA may produce epigenetic effects. Long-term induction of PDH and other oxidative pathways related to glucose metabolism could contribute to increase reactive oxygen species and mitochondrial stress [27]. However, no evidence of carcinogenetic effect is reported in clinical studies, when DCA is administered in cancer therapy.

4. Synergistic Effect of DCA and Chemotherapeutic Agents

Combining different drugs is a well-accepted strategy to produce a synergistic beneficial effect in cancer therapy, reducing drug dosage, minimizing toxicity risks, and overcoming drug resistance. Coadministration of DCA and traditional chemotherapeutic agents has been purposed and tested in several cancer models (Table 1). DCA treatment seems to improve the efficacy of chemotherapy by inducing biochemical and metabolic alterations, resulting in significant changes of cancer cells’ energetic balance. A study performed in non-small-cell lung cancer (NSCLC) showed both in vitro and in vivo that coadministration of DCA with paclitaxel increased the efficiency of cell death through autophagy inhibition [32]. An effective combination of DCA and doxorubicin (DOX) was tested in HepG2 cells, demonstrating the ability of DCA to disrupt cellular antioxidant defences, thus favouring oxidative damage in turn triggered by DOX treatment [33]. There is a strong association between PDK overexpression and chemoresistance; thus, it is conceivable that PDK inhibition might help to resensitize cancer cells to drugs. PDK2 isoform overexpression was associated to paclitaxel resistance in NSCLC. Interestingly, DCA combination with paclitaxel was more effective in killing resistant cells than either paclitaxel or DCA treatment alone [34]. Similarly to NSCLC, an interesting in vivo study performed in advanced bladder cancer showed an increased expression of PDK4 isoform in high grade compared to lower-grade cancers and cotreatment of DCA and cisplatin dramatically reduced tumour volumes as compared to either DCA or cisplatin alone [35]. A recent study confirmed the ability of DCA to revert PDK4-related chemoresistance also in human hepatocellular carcinoma (HCC) [36].

Tumour entityModel systemChemotherapy drug coadministered with DCAMechanism of actionOutcomeReferencesLung cancerA549-H1975 cell lines/xenograft modelPaclitaxelAutophagy inhibitionEfficacious cancer chemotherapy sensitization[32]HepatocarcinomaHepG2 cell lineDoxorubicinAntioxidant defence disruptionIncreased cellular damage by oxidative stress induction[33]Lung cancerA549 cell linePaclitaxelIncreased chemosensitivity through PDK2 inhibitionPaclitaxel resistance overcome[34]Bladder cancerHTB-9, HT-1376, HTB-5, HTB-4 cell lines/xenograft modelCisplatinIncreased chemosensitivity through PDK4 inhibitionIncreased cell death of cancer cells and potential therapeutic advantage[35]HepatocarcinomaSphere cultures from HepaRG and BC2 cell linesCisplatin, sorafenibIncreased chemosensitivity through PDK4 inhibitionImproved therapeutic effect of chemotherapy by mitochondrial activity restoration[36]

Table 1List of reports suggesting beneficial effect of DCA and chemotherapy coadministration in several types of cancers.

5. Synergistic Effect of DCA and Other Potential Anticancer Drugs

A consistent body of literature suggests positive effects of DCA coadministration with compounds currently employed to treat other diseases but showing anticancer properties in several cancer models (Table 2). Contemporary administration of DCA and the antibiotic salinomycin, recently rediscovered for its cytotoxic properties as a potential anticancer drug, has been tested in colorectal cancer cell lines. Their treatment seems to exert a synergistic cytotoxic effect by inhibiting the expression of proteins related to multidrug resistance [37]. Cancer cells lacking metabolic enzymes involved in arginine metabolism may result to sensitivity to arginase treatment. Interestingly, a combined administration of recombinant arginase and DCA produces antiproliferative effects in triple-negative breast cancer, due to the activation of p53 and the induction of cell cycle arrest [38]. COX2 inhibitors, primarily used as anti-inflammatory drugs, have been recently suggested as antitumor drugs because of their antiproliferative activity. An intriguing study performed in cervical cancer cells showed the inability of DCA to kill cervical cancer cells overexpressing COX2 and demonstrated that COX2 inhibition by celecoxib makes cervical cancer cells more sensitive to DCA both in vitro and in vivo experiments [39]. Since DCA fosters oxidative phosphorylation by decreasing glycolytic activity, the combination of DCA with other drugs enhancing a state of glucose dependence may be a promising strategy. Such an approach has been tested in head and neck cancer in which the administration of propranolol, a nonselective beta-blocker able to affect tumour cells’ mitochondrial metabolism, produced glycolytic dependence and energetic stress, making cells more vulnerable to DCA treatment [40]. Similar results were obtained in melanoma cells in which the administration of retinoic acid receptor β (RARβ) inhibitors confer sensitization to DCA [41]. A positive effect of DCA coadministration with metformin, a hypoglycaemic drug widely used to treat diabetes was demonstrated in a preclinical model of glioma [42] as well as in a low metastatic variant of Lewis lung carcinoma (LLC) [43]. Jiang and colleagues investigated the effects of phenformin, a metformin analog, and DCA in glioblastoma, demonstrating that contemporary inhibition of complex I and PDK by phenformin and DCA, respectively, decreased self-renewal and viability of glioma stem cells (GSCs), thus suggesting their possible employment to affect cancer stem cell fraction [44].

DrugMain functionTumour entityModel systemOutcomeReferencesSalinomycinAntibioticColorectal cancerDLD-1 and HCT116 cell linesInhibition of multidrug resistance-related proteins[37]ArginaseArginine metabolismBreast cancerMDA-MB231 and MCF-7/xenograft modelAntiproliferative effect due to p53 activation and cell cycle arrest[38]COX2 inhibitorsInflammationCervical cancerHeLa and SiHa cell lines/xenograft modelCancer cell growth suppression[39]PropranololBeta-blockerHead and neck cancermEERL and MLM3 cell lines/C57Bl/6 miceGlucose dependence promotion and enhancement of chemoradiation effects[40]RARβ inhibitorsVitamin A metabolismMelanomaED-007, ED-027, ED-117, and ED196 cell linesGlucose dependence promotion and sensitization to DCA[41]MetforminDiabetesGlioma, Lewis lung carcinomaXenograft model; LLC/R9 cellsProlonged lifespan of mice with glioma; severe glucose dependency in tumour microenvironment[4243]PhenforminDiabetesGlioblastomaGlioma stem cells/xenograft modelSelf-renewal inhibition of cancer stem cells[44]

Table 2List of drugs with their main function tested in combination with DCA in several cancer models.

6. Combined Use of DCA and Natural Compounds

The clinical employment of natural compounds represents a promising novel approach to treat several diseases [45]. An increasing body of literature supports the detection, among natural compounds, of biologically active substances isolated by plants, mushrooms, and bacteria or marine organism that show beneficial effects for human health [4648]. The assumption of natural compounds or their derivatives seems to represent an encouraging approach to prevent cancer initiation or recurrence, and it is generally called chemoprevention [49]. Moreover, natural substances produce beneficial effects in cancer therapy when coadministered with other drugs, showing their ability to overcome drug resistance, to increase anticancer potential, and to reduce drug doses and toxicity [5051]. Interestingly, the coadministration of DCA and natural compounds has been recently purposed. A study investigated the combined effect of DCA with essential oil-blended curcumin, a compound with beneficial properties both in prevention and treatment of cancer [52], demonstrating an anticancer potential against HCC [53]. In particular, the combination of both compounds synergistically reduced cell survival, promoting cell apoptosis and inducing intracellular ROS generation. Betulin, a natural compound isolated from birch bark, is already known for its antiproliferative and cytotoxic effects against several cancer cell lines [5456]. An in vitro investigation of the antitumor activity of betulin derivatives in NSCLC confirmed its ability to inhibit in vivo and in vitro growth of lung cancer cells, blocking G2/M phase of the cell cycle and inducing caspase activation and DNA fragmentation. Interestingly, betulin derivative Bi-L-RhamBet was able to perturb mitochondrial electron transport chain (ETC), inducing ROS production. Given the property of DCA to increase the total oxidation of glucose in mitochondria via the Krebs cycle and ETC, the authors combined Bi-L-RhamBet with DCA, demonstrating its significant potentiated cytotoxicity [57].

7. DCA and Radiosensitization

Radiotherapy represents a further strategy to treat cancer and provides a local approach by the administration of high-energy rays [58]. The main effect of radiation is the induction of ROS with a consequent DNA damage, chromosomal instability, and cell death by apoptosis [59]. However, several tumours show or develop radioresistance that is responsible for radiotherapy failure and high risk of tumour recurrence or metastasis [60]. Several factors may be responsible of radioresistance [61]. Among these, hypoxia, a common condition of tumour microenvironment characterized by low oxygen levels and reduced ROS species generation, can block the efficacy of ionizing radiations [62]. Increasing tumour oxygenation so to favour a considerable amount of ROS [63] or directly induce ROS production may therefore represent a strategy to increase radiosensitization [6465]. In this setting, DCA administration, known to induce ROS production [1166], could represent a strategy to overcome tumour radioresistance. Moreover, metabolic alterations featuring cancer development are known to affect radiosensitivity [6768]. Therefore, targeting cancer metabolic intermediates may represent a strategy to improve a selective cancer response to irradiation [69]. The efficacy of DCA to increase radiation sensitivity has been already demonstrated both in glioblastoma cells [70] and in oesophageal squamous cell carcinoma [71]. More recently, it was demonstrated that DCA increases radiosensitivity in a cellular model of medulloblastoma, a fatal brain tumour in children, inducing alterations of ROS metabolism and mitochondrial function and suppressing DNA repair capacity [72]. Since the role of immunotherapy in the restoration of the immune defences against tumour progression and metastasis is arousing great attention in the last years [73], Gupta and Dwarakanath provided a state of the art of the possible effects of glycolytic inhibitors, including DCA, on tumour radiosensitization, focusing their attention on the interplay between metabolic modifiers and immune modulation in the radiosensitization processes [74]. Interestingly, they reported the ability of DCA to promote immune stimulation through the inhibition of lactate accumulation, further sustaining its utilization as adjuvant of radiotherapy.

8. DCA and New Drug Formulations

There is a growing interest in designing new drug formulations so to improve drug delivery, increasing the efficacy and reducing the doses and consequently undesirable effects. In this setting, drug delivery systems (DDSs) represent a new frontier in the modern medicine [75]. DDSs offer the possibility to create a hybrid of metal-organic frameworks (MOFs), combining the biocompatibility of organic system to the high loadings of inorganic fraction [76]. Several lines of evidence suggest an efficient functionalization of nanoparticles with DCA. Lazaro and colleagues [77] explored different protocols for DCA functionalization of the zirconium (Zr) terephthalate (UiO-66) nanoparticles. They demonstrated the cytotoxicity and selectivity of the same DDSs against different cancer cell lines. Moreover, they excluded a possible response of the immune system to DCA-MOF in vitro. The same group later showed the possibility to load Zr MOFs with a second anticancer drug, such as 5-fluorouracil (5-FU), so to reproduce the synergistic effect of the two drugs [78]. Zirconium-based MOF loaded with DCA was also purposed as an attractive alternative to UiO-66, showing selective in vitro cytotoxicity towards several cancer cell lines and a good toleration by the immune system of several species [79]. Recently, Štarha et al. [80] synthesized and characterized, for the first time, half-sandwich complexes containing ruthenium or osmium and DCA (Figure 2(a)). Both Ru-dca and Os-DCA complexes were screened in ovarian carcinoma cell lines, demonstrating to be more cytotoxic than cisplatin alone. Both complexes were able to induce cytochrome c (Cytc) release from mitochondria, an indirect index of apoptosome activation and seemed to be less toxic towards healthy primary human hepatocytes, thus indicating selectivity for cancer over noncancerous cells. Promising results were also obtained in triple-negative breast cancer cells [81]. Rhenium (I)-DCA conjugate has demonstrated an efficient penetration into cancer cells and a selective accumulation into mitochondria, inducing mitochondrial dysfunction and metabolic disorders [82]. In the recent years, several multiactive drugs have been designed to contemporary target different intracellular pathways using a single formulation. A safe, simple, reproducible nanoformulation of the complex doxorubicin-DCA (Figure 2(b)) was successfully tested in a murine melanoma model, showing an increase in drug-loading capability, lower side effects, and enhanced therapeutic effect [83]. Dual-acting antitumor Pt (IV) prodrugs of kiteplatin with DCA axial ligands have been synthesized (Figure 2(c)), characterized, and tested in different tumour cell lines and in vivo [84]. To overcome cancer resistance, triple action Pt (IV) derivatives of cisplatin have been proposed as new potent anticancer agents, able to conjugate the action of cisplatin, cyclooxygenase inhibitors, and DCA (Figure 2(d)) [85]. A novel complex containing DCA, Platinum, and Biotin (DPB) has been successfully tested, exhibiting multifacet antitumor properties (Figure 2(e)). Authors demonstrated the ability of such a prodrug to affect energy metabolism, to promote apoptosis, and to interact with DNA. The high selectivity of biotin for cancer cells minimizes the detrimental effects on normal cells and improves the curative effect on tumours [86]. Features and experimental evidence of the main classes of compounds are summarized in Table 3.

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(e)Figure 2New drug formulations containing DCA. (a) Schematic representation of Os-DCA and Ru-DCA complexes [81]. (b) Doxorubicin (DOX)-DCA complex [83]. (c) Dual action Pt prodrugs of kiteplatin and DCA [84]. (d) Examples of triple action Pt(IV) derivatives of cisplatin containing DCA (red), derivatives of cisplatin (black), and COX inhibitors (green) [85]. (e) Chemical structure of DPB containing DCA (red), biotin (blue), and Platinum (Pt) complex (black) [86].

Class of drug formulationFeaturesIn vitro testsIn vivo testsExperimental evidenceReferencesMetal-DCA frameworks (no platinum)Metal ions linked to organic ligands into porous scaffoldsMCF-7/MDA-MB-231 (breast)
HeLa/LO2 (cervix)
A2780 (ovary)
A549/NCl-H1229 (lung)Breast mouse modelsBiocompatibility selective cytotoxicity
Immune system compatibility
Low mutagenicity[7782]Doxorubicin-DCA conjugateComplexes of DCA and chemotherapy drugsB16F10 (melanoma)Sarcoma and melanoma mouse modelsSelective cytotoxicity safety
In vivo antitumour efficiency[83]Platinum prodrugs with DCAPlatinum core associated to DCA and others drugsMCF-7 (breast)
LoVo/HCT-15/HCT116 (colon)
A549 (lung)
BxPC3/PSN-1 (pancreas)
A375 (melanoma)
BCPAP (thyroid)
HeLa (cervix)
HepG2 (hepatocarcinoma)Lung carcinoma mouse modelsSelective cytotoxicity multiple action
Increased cellular uptake[8486]

Table 3Properties of the main classes of DCA drug formulations tested in cancer cell lines and in vivo models with experimental evidence related.

9. Other Proposed Mechanisms of Action of DCA

The metabolic shift from glycolysis to glucose oxidation due to the inhibition of PDK and the consequent activation of PDH is the best-known and well-accepted molecular effect of DCA administration. The consequent biochemical alterations, including ROS increase and mitochondrial membrane potential variation, may be responsible for proliferation arrest and cancer cell death, thus explaining DCA beneficial potential in cancer treatment [9]. However, the molecular intermediates activated after DCA administration are still unknown. It is conceivable that such a small molecule might directly or indirectly affect other cellular and molecular targets (Figure 3), displaying other mechanisms of action, so to explain its efficacy also in cellular models where it does not produce the expected metabolic shift [12]. A proteomic approach applied to cells of lung cancer demonstrated the ability of DCA to increase the concentration of every TCA intermediate while it did not affect glucose uptake or the glycolytic process from glucose to pyruvate [87]. In the attempt to shed light to DCA mode of action, Dubuis and colleagues used a metabolomics-based approach on several ovarian cancer cell lines treated with DCA and found a common marked depletion of intracellular pantothenate, a CoA precursor, as well as a concomitant increase of CoA, thus suggesting DCA ability to increase CoA de novo biosynthesis. Since high concentrations of CoA resulted to be toxic for cells, this metabolic effect could be responsible of cancer cell toxicity mediated by DCA [88]. A very recent work by El Sayed et al. introduced a novel evidence-based hypothesis, suggesting that DCA efficiency against cancer may derive from its ability to antagonize acetate [89], known to be an energetic substrate for glioblastoma and brain metastases, able to enhance DNA, RNA, and protein synthesis and posttranslational modifications, thus favouring cell proliferation and cancer progression. Moreover, high acetate levels are associated to anticancer drug resistance [90]. It has been shown that DCA is able to revert metabolic alterations induced by acetate by restoring physiological serum levels of lactate and free fatty acid and potassium and phosphorus concentration. According to the authors, thanks to a structural similarity to acetate, DCA could inhibit metabolic effects driven by acetate, responsible for cancer cell growth and chemoresistance [89]. Another possible additional effect of DCA could be pH modulation. pH level modulation is known to affect proliferation and apoptosis processes [91] as well as chemotherapy sensitivity [92]. DCA treatment may both increase and reduce intracellular pH. A secondary effect of pyruvate redirecting into the mitochondria by DCA would be lactate reduction and a consequent increase in intracellular pH. On the other side, DCA is able to decrease the expression of monocarboxilate transporters and V-ATPase with a consequent reduction of pH, and this especially occurs in tumour cells, expressing higher amount of these carriers, compared to normal counterparts [93]. Given the ability to induce rapid tumour intracellular acidification, Albatany et al. [94] speculated about a possible employment of DCA as a tracker in in vivo imaging of a glioblastoma murine model and supported a therapeutic use of DCA since intracellular acidification is known to induce caspase activation and DNA fragmentation of cancer cells [95]. Animal models allow to identify a possible further molecular target of DCA. Experiments performed in rats highlighted the ability of DCA to inhibit the expression of the renal cotransporter Na-K-2Cl (NKCC) in the kidney of rats [96]. As NKCC is an important biomarker of extracellular and intracellular ion homeostasis regulation and participates in cell cycle progression, it plays an important role in cancer cell proliferation, apoptosis, and invasion. Belkahla et al. [97] investigated the interplay between metabolism targeting and the expression of ABC transporters, responsible for drug export from cells and a consequent multidrug resistance, and found that DCA treatment is able to reduce gene and protein expression of ABC transporters in several tumour cells expressing wild type p53, both in vitro and in vivo [98]. It has been already demonstrated the ability of DCA to induce differentiation through the modulation of PKM2/Oct4 interaction in glioma cells [99]. The resulting reduction of Oct4 transcription levels was associated to a reduction of stemness phenotype and a significant increased sensitivity to cell stress. This observation lets to hypothesize a potential role of DCA against cancer stem cells (CSCs).

Figure 3Other proposed mechanisms of action of DCA. DCA’s main mechanism is to inhibit pyruvate dehydrogenase kinase (PDK), leading to pyruvate dehydrogenase (PDH) activation and fostering oxidative phosphorylation (1). DCA also increases each Krebs cycle intermediate concentration (2) [87]. DCA induces cell toxicity via de novo synthesis of CoA (3) [88]. DCA may antagonize acetate (4) [90]. DCA modulates intracellular acidification (5) [9394]. DCA inhibits Na-K-2Cl cotransporter (6) [96]. DCA downregulates gene and protein expression of ABC transporters (7) [97]. DCA reduces the expression of self-renewal-related genes and affects cancer stem cell fraction (8) [99].

10. DCA and Cancer Stem Cells

There is a growing interest in targeting cancer stem cells (CSCs) which seem to be the main responsible for tumour relapse [100]. CSCs share the ability of self-renewal with normal stem cells and can give rise to differentiating cells, responsible for tumour initiation as well as malignant progression [101]. A low proliferation rate and specific metabolic profile contribute to make CSCs resistant to conventional chemotherapy [102]. An urgent need emerged in the developing of new therapeutic agents able to affect cancer stem cell viability [103] in order to completely eradicate the tumour mass. An extensive body of literature is focusing the attention on the metabolic phenotype of CSCs, which seem to differ from differentiated cancer cells and could represent a therapeutic target [104108]. In this setting, the possible sensitivity of CSC fraction to DCA has been hypothesized and tested in different cancer models. Embryonal carcinoma stem cells represent one of the more appropriate models for the study of CSC maintenance and differentiation and the identification of drugs and molecules able to modulate these processes [109]. Studies performed on embryonic stem cells (ESCs) constitute preliminary important proofs supporting a possible efficacy of DCA [110]. Interestingly, DCA treatment of ESCs promotes loss of pluripotency and shifts towards a more active oxidative metabolism, accompanied by a significant decrease in HIF1a and p53 expression [111]. Vega-Naredo et al. [112] described the importance of mitochondrial metabolism in directing stemness and differentiation in such a model. They characterized the metabolic profile of stem cell fraction and guessed the less susceptibility of stem phenotype to mitochondrial-directed therapies. Forcing CSCs towards an oxidative metabolism by DCA treatment enabled departure from stemness to differentiation. Several reports support the existence of CSCs in glioma [113114], and the efficiency of DCA to hit CSCs has been extensively evaluated in such a cancer type, so difficult to treat with conventional therapies and characterized by low rates of survival. Already in 2010, Michelakis and colleagues had suggested, both in vitro and in vivo, DCA ability to induce apoptosis of cancer stem cell fraction [26]. A rat model of glioma, recapitulating several features of human glioblastoma, confirmed the efficacy of DCA to potentiate apoptosis of glioma CSCs, characterized by a significant glycolytic pathway overstimulation, compared to normal stem cells [115]. Also, Jiang et al. investigated the effect of DCA on the small population of glioma stem cells (GSCs) isolated from glioblastoma, demonstrating a reduction of self-renewal properties and an increase in cell death percentage [44]. Moreover, an in vivo test on mice bearing DCA-treated GSC-derived xenografts showed a significant increase in overall survival. DCA treatment was also tested in melanoma stem cell fraction, and the derived bioenergetics modulation was able to counteract protumorigenic action of a c-Met inhibitor [116]. A very recent work performed on human hepatocellular carcinoma identified PDK4 overexpression in spheres originated from cancer cells, featuring a defined stem-like phenotype. Interestingly, DCA treatment was able to reduce cell viability both of cancer-differentiated cells and cancer stem cells and reversed chemoresistance to conventional therapy [36]. Our group has recently experienced the ability of DCA to reduce the expression of cancer stem cell markers CD24/CD44/EPCAM in a pancreatic cancer cell line as well as to compromise spheroid formation and viability [12], further corroborating data obtained in other cancer models. Together with chemoresistance, also radioresistance represents a limit to an efficient cancer treatment, and CSCs seem to be responsible for such refractoriness [117]. Sun et al. demonstrated the ability of DCA to increase radiosensitivity of medulloblastoma cells by affecting stem-like clones, reducing the expression percentage of CD133-positive cells and reducing sphere formation [72]. Moreover, in the same cellular model, they showed an altered mechanism of DNA repair induced by DCA able to explain the increased effectiveness of radiotherapy.

11. Conclusions

Targeting cancer cell metabolism represents a new pharmacological approach to treat cancer. DCA ability to shift metabolism from glycolysis to oxidative phosphorylation has increased the interest towards this drug already known for its anticancer properties. The evidence accumulated in the last years confirms the capability of DCA to overcome chemo, radioresistance in several cancer types and lets to hypothesize additional cellular targets able to explain its skill to kill cancer cells. There is a need to design further clinical studies now limited to poor-prognosis patients with advanced, recurrent neoplasms, already refractory to other conventional therapies. Its potential efficacy against cancer stem cells as well as the development of new drug formulations takes us closer to reach an effective clinical employment of DCA.

Acknowledgments

The authors declare no conflict of interest.

This work was supported by Current Research Funds, Italian Ministry of Health, to IRCCS-CROB, Rionero in Vulture, Potenza, Italy.

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Copyright © 2019 Tiziana Tataranni and Claudia Piccoli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Where to buy Sodium Dichloroacetate DCA (NaDCA)

Sodium Dichloroacetate NaDCA available on line will cost $2-$3 per day.

You have obviously arrived here because yourself or someone in your life has cancer. Please take a minute and go to the home page of this site and read some of the published medical journal articles on DCA. Get an understanding of the Warburg effect the scientific principle behind this discovery, and you will then not question whether DCA works! This is not a hoax, this is not just one major University making the claim, there are papers published on this site from many major Universities.

The American Cancer Society warns you that these sellers are out to fleece desperate people of their money”.If you do your research you will be disappointed to find that these organizations you should be able to trust are actually working hand in hand with the Pharma companies to suppress any non pharma cancer treatment.

As we have said on this site NaDCA is a very simple molecule resembling vinegar and is documented in peer reviewed medical journal studies as being as safe to take for healthy people as it is for sick people.

If you are still questioning whether DCA works you need to only answer for yourself 2 questions.

1) Is the Warburg effect really the law of cancer? (meaning that all normal cells achieve respiration from Oxygen and all cancer cells receive respiration from glucose) PROOF….. The Warburg effect is the science behind the PET scan machine (patient is injected with radio active glucose and cancer cells light up on the screen) What Wargurg discovered was that when a cell became a cancer cell (reverted to glucose respiration) the mitochondria shut down. The mitochondria is the control center of a cell, every day as our cells divide the mitochondria looks at the cell and if it’s dna is not correct, (a bad cell) it kills itself through a process known as apoptosis. Every day our bodies expel millions of bad cells through apoptosis.  Therefore a cancer cell is simply a cell that achieves energy from glucose and continues to divide and multiply without our bodies being able to kill it through the normal process of apoptosis.

2) As the University of Alberta research claims does DCA turn the mitochondria of the cancer cell back on, allowing it to recognize itself as a bad cell and trigger apoptosis? The answer is YES! Read the published articles on the home page and believe in your own research, not what someone you think should know is telling you. At the very least use this information to start questioning your treatment or the treatment of a loved one suffering from cancer.

NaDCA advocate Martin C. Winer has come up with a protocol combining NaDCA with a supplement called Avemar, the protocol can be found here, this may be a  a good option for anyone in later stage cancer or has had orthodox treatment and a weakened immune system.http://www.martincwiner.com/dca-and-avemar-a-theoretical-protocol-for-cancer/

This protocol has been  tested by the Medicor Cancer Clinic in Toronto with great results.

There appear to be 3 main sites on line selling NaDCA. One thing you need to know is that these sites can not buy the NaDCA in North America or Europe. From what we have been able to find, the only supply sources at present are in China. This is due to the FDA , Health Canada and the European health agencies restrictions placed on Sodium dichloroacetate in 2007. The claimed intent of restricting NaDCA , (which is about as harmful as taking to much baking soda) being to protect us from ourselves.

For years we have seen many media reports of safety issues involving Chinese products. However, with what we have discovered about the ethics of North American drug companies and their ability to influence what the media reports to us, we began to question how bad quality issues could be. If you look into the Chinese pharmaceutical industry you will find they operate under very strict guidelines, with as much or more oversight as facilities in North America.

The truth is if there was as much medical journal published evidence that cocaine cured cancer, as there is regarding DCA, you would be asking everyone you knew if they knew a dealer! If the quality is your concern one of the online companies has every batch randomly tested in Canada. www.certifieddca.com

The NaDCA clinical trails are supplied world wide by a company called TCI America http://www.tciamerica.com/catalog/D1719.html and have been for decades, they do not sell to the general public. It also would appear from TCI’s sales site that the product they sell also comes from Asia. Medicor Cancer Center in Toronto claims to be purchasing their NaDCA from the USA which we would guess comes from TCI.

If you are going to take NaDCA, 100 grams is about a 90 day supply for most people treating cancer. As a supplement to prevent a cancer recurrence or just to keep you healthy 100 grams is about a 200 day supply at a half gram per day.

Keep in mind that there has not been a large demand for DCA and world wide supply is limited, one pharmaceutical company we spoke with indicated their excess available supply at 900 kg per year, that would only treat  9,000 people for 3 months. We also found that the difference in price varies in china, we found chemical companies that manufacture technical grade product are also now offering pharmaceutical grade, however pharmaceutical grade from an actual pharmaceutical company is more expensive which can be the price difference between the 3 major suppliers.

Since the amount taken is based on body weight it is not necessary to spend the extra for the product in capsules as you would only be breaking them apart to get the proper weight.

The other thing to consider is that all sites selling NaDCA were closed down by the FDA in 2007 and this could happen again, our point is if you are thinking of using NaDCA it may become hard to get as more people find out about it.

There have been some issues reported on The DCA Site regarding problems with DCA coming in from Mexico, if the price seems too cheap there could be good reason for it.

The www.dcasite.com is your best source for getting dosage information from others that have experience with NaDCA. Do keep in mind that social media people from the Pharma industry commonly take part in the chats and online discussions just to confuse people.

The top sites supplying NaDCA to the public are below,  However It has recently come to our attention that  www.shouldyoubuydca.com which has been a site used by Pharma DCA as a “we don’t sell DCA but buy this one site”  has claimed recently that they are an anonymous crusader for DCA and tested all the other suppliers product and only Pharma DCA and Sigma Aldrich passed, which of course Sigma Aldrich does not sell to the public. The site recommends people do not buy the other suppliers DCA now claiming their products have high Bromine counts however they provide no testing results. (their claim according to their site February 15,2015 as they may change it) What tells me no testing ever took place is that they report the Pure DCA and Certified dca as having 170mg per kg and 148mg per kg of bromine.  Had they actually tested, firstly the results would be reported as PPM (parts per million) or ug not mg per kg. They report Pharma dca and Sigma Aldrich as <2. less than 2 what? it should be less than 2 ug/kg which is also what the other 2 suppliers bromine levels are had they reported correctly  .170ug and .148 ug both <2 if reported in the same unit of measure as their product and Sigma Aldrich (information directly from Sigma Aldrich’s web site).

We have over the last three years received various comments and complaints about suppliers. We do not approve them without proper evidence that there is an issue with the supplier that could harm people. We set up this site as a place where people could find relative published medical Journal studies and form their own conclusions. We have long recommended these 3 sites as a source for DCA as they have been around the longest. What people may not realize is that these sites get regular orders from government buildings where the product is tested not for your protection but in an effort to catch a supplier selling something other than +99% pure dca. Believe me when I say if one of these suppliers was offering unsafe product you would have read about it everywhere, it would be a huge media circus.

We did have product tested from these 3 suppliers about 2 months ago and all passed, which I reported on this site, however I decided to take it down due to liability if there was an unexpected problem with a batch they put out. The sad part is that DCA does work and yet it is hard to get people to read through the medical journal articles and reach their own conclusions without second guessing themselves. There is a huge amount of propaganda put out by the Pharma companies disguised as Medical Websites and literally hundreds of pharma employees participating in social media sites using fear to keep people away from DCA. The last thing DCA needed is some idiot supplier trying to spread more false fear about other suppliers!

We still recommend the 3 suppliers below  strictly based on the fact that they have been around for more than 3 years and we have tested the products ourselves in the past.

www.certifieddca.com

www.pharmadca,com

www.puredca.com

We will continue to purchase from www.certifieddca.com simply because we have always had great service and each batch is tested in Canada for purity and any solvents or heavy metals. They also send you a test report for the batch once you have ordered. It is a little more expensive, about 20-40 cents per day. However they have always been very help full with questions. I don’t want to be seen as promoting them it is just the only supplier we have experience with, and as I said above, as far as quality goes It is my opinion that all 3 are safe to buy from.

Having the product tested yourself can cost up to $750 depending on where you go. If it is out of your budget by all means buy from whichever company you can afford.

If you do start taking NaDCA please let us know about your progress as it may help others as they try to make a decision that is best for them.

DCA Papers and Clinical Trials

DCA papers and clinical trials

For almost a decade there has been a growing interest in Dichloroacetate potential to successfully get rid of cancer while causing minimal harm to healthy organs. DCA is a relatively cheap substance which cannot be patented by the pharmaceutical industry, thus it could not generate profit for private drug companies. Right now, because of this reason, Dichloroacetate isn’t receiving enough funding and attention which it deserves.

Despite that, there are plenty of ongoing and completed studies which examine the facts of DCA appliance for therapy. This site will present a handful of completed scientific investigations and will constantly update you with the most recent publications related to the subject.

MEDLINE is the largest medical database in the world, and contains information on published DCA research. This database can be searched free of charge for those interested in reading DCA research, or the summaries of the DCA publications.

Further research to determine how well DCA works against various cancers within the human body is ongoing. 

DCA research

Further research

 

DCA History

DCA history

Since 1973 Sodium Dichloroacetate (DCA) was used to treat various mitochondrial disorders. It inhibits the activity of pyruvate dehydrogenase kinase, and reduces the accumulation of lactate in body tissues. Its usage for treating lactic acidosis has been successful and is still continued to this day, it is used in several research and medical centers in the United States and Canada.

The majority of the people who have used DCA are children with congenital mitochondrial disorders. The use of the drug could resume the normal function of the cellular enzymes and prevent further neurological damage, mental disability, microcephaly, blindness and movement disorders. Dichloroacetate safety has been confirmed long before the idea, that it could be helpful for someone who has cancer.
In 1920s German biochemist Otto Warburg found abnormalities in metabolism in cancer cells. Normal cells obtain energy by glucose oxidation, which requires the presence of oxygen. Cancer cells depend on glycolysis to obtain energy, and it can occur without the presence of oxygen, but is dependent on the availability of sugar. Cancer cells favor glycolysis even in the presence of adequate oxygen for oxidative phosphorylation, leading to a voracious appetite for glucose. This phenomenon prompted Warburg to propose that mitochondrial malfunction was the primary cause of cancer. Sodium Dichloroacetate (DCA) works by inhibiting the
“Warburg Effect”.

DCA forces cancer cell to abandon its preferred metabolic process and also induces apoptosis, or cellular suicide. The reason cancer is so fast growing is that the mitochondria have been deactivated, so the cells evade apoptosis and are able to grow in the absence of oxygen. DCA reverses this. In effect, DCA directly causes cancer cell apoptosis and works synergistically with other cancer therapies.

• In 2007 dr. Evangelos Michelakis of the University of Alberta in Canada published a research paper that renewed interest in DCA. It showed potential of DCA to shrink cancer tumors. In the study DCA was administered to rats with transplanted tumor cells (brain, breast and lung). DCA killed cancer cells without affecting healthy cells. The rats’ tumors decreased by up to 70 percent in three weeks of DCA treatment:
A Mitochondria-K Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

Other researchers have followed and confirmed anti-cancer effects of DCA. Yet most of the studies have been done on cell cultures in the lab, and not on the cancer patients themselves. But results are very consistent, suggesting DCA is effective against a wide variety of cancer types.

• In 2013, Phase 1 clinical trial of dichloroacetate (DCA) was completed in Canada. It showed that DCA is feasible and well tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases:
Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

• In another study, five glioblastoma multiforme patients were treated with oral DCA for up to 15 months. The research showed clinically promising results in four of the five patients:
Metabolic modulation of glioblastoma with dichloroacetate

• Medicor Cancer Center in Canada is a cancer clinic currently offering DCA therapy for it’s patients. It has published several case studies about the safety and effectiveness of DCA. Its real-world Observational DCA patient data is available to the public.

• Till this day, there are several ongoing clinical studies and a lot of pre-clinical research going on. Recently it has been noted that DCA can work by itself, however, it provides the maximum results in combination therapy with other drugs for a prolonged time period.

Methods and Supplements for Preventing DCA Side Effects

Methods and supplements for preventing DCA side effects

When you begin your Sodium dichloroacetate regimen, it is crucial that you take supplementation which provides protective benefits. This way you minimize the chance for developing reversible peripheral neuropathy asas well as other adverse reactions related to the nervous system.

Below you will find a list of supplements which are essential or recommended for a pleasant DCA usage experience with the lowest achievable side effect probability.

▪ Vitamin B1 – thiamine.(Necessary)
(take one and a half 100mg capsules / tablets twice a day. Take it before breakfast and before lunch.
An alternative way – take 100 mg three times a day. Total – 300 mg)

The B group vitamin thiamine appears to have a protective effect against peripheral neuropathy. This food supplement can be used not only for DCA induced neuropathy but also for other neuropathies which are caused by diabetes and chronic alcohol abuse. (Ref.)

We recommend using benfotiamine because it can be absorbed over five times better than the ordinary thiamine form.

In addition, the newest research claims that Vitamin B1 can have an antiproliferative effect on malignant cells. (Ref.)

▪ Alpha–Lipoic acid. (Necessary)
(take one 300 mg R+/S- capsule/tablet three times a day or take one 150 mg R+ capsule/tablet three times a day. Take it before breakfast, before lunch and before dinner. Total – 900 mg (R+/S-) or 450 mg (R+))

α-Lipoic acid is a strong antioxidant, it helps avoiding and controlling symptoms related to neuropathy. The supplement can lower anxiety, memory problems as well as help keeping away from peripheral neuropathy manifestations such as tingling, burning, painful sensations and numbness. (Ref.)

You can use smaller doses if you’re taking R-form α-Lipoic acid.
If you have Racemate α-Lipoic acid (which is a mix of R and L forms), you should take a twice larger dose to fulfill your daily goal.

Don’t take α-Lipoic acid if you’re receiving chemotherapy or radiotherapy.
α-Lipoic acid has a strong antioxidative effect that can interfere with the effectiveness of chemotherapy. For this reason, we recommend staying away from this supplement a couple of days before the chemo, during the treatment and 1 week after the chemotherapy. (Ref.)

α-Lipoic acid also can decrease the effectiveness of radiotherapy. This is why we recommend avoiding taking it for several days before, during and 2 week after these procedures.

▪ Acetyl L-Carnitine. (Recommended)
(take on 600mg capsule / tablet three times a day. Take it before breakfast, before lunch and before dinner. Total – 1800 mg)

The majority of scientific studies claims that Carnitine can be an effective aid to lower peripheral neuropathy. Acetyl L-Carnitine is also an attractive option because its longtime usage does not cause any side effects and carries no health risk. (Ref1.), (Ref2.), (Ref3.)

α-Lipoic acid and Acetyl L-Carnitine both appear to have a synergistic effect at preventing neuropathy.

On rare occasions, Sodium dichloroacetate administration can result in heartburn or nausea. If this is the case, try taking DCA after you eat a little bit of food and drink some fluids to avoid your stomach becoming irritated.

If that did not resolve the problem, you should try taking medications that lower gastric acid secretion – proton pump inhibitors.
Any type of PPI is acceptable provided the fact that they don’t have any major differences.

▪ Pantoprazole. 
(take one 40mg tablet per day, at the same time. Take it at least 30 minutes before your meal and DCA.)

For convenience purposes, we recommend using Pantoprazole because it doesn’t seem to have any poor interactions with other medications.

If you began experiencing moderate side effects or develop a stronger form of peripheral polyneuropathy – stop taking DCA until the adverse reactions become acceptable or disappear completely.

All Sodium dichloroacetate side effects are reversible.

When you stop taking DCA, the majority of the side effects disappear in several days. Peripheral neuropathy can take up to a week or, in rare occasions, a couple of weeks to resolve completely. (Ref.)

Additionally, if you have an opportunity – we recommend regularly performing blood tests and checking the blood serum for tumor marker levels.

UltrasoundComputer tomography scansMagnetic resonance imagingPositron emission tomography are imaging tests that can provide more information about the dynamics of your overall health, and most importantly, the size changes of your cancer.

DCA Safety and Side Effects

DCA safety and side effects


Sodium dichloroacetate is considered to be a fairly safe alternative cancer treatment. There have been no cases recorded for DCA to be a cause of death.

Before we begin, we should bear in mind that Sodium dichloroacetate has already demonstrated  success in dealing with ‘‘Lactic acidosis in children with congenital mitochondrial defects“  for some time. The first scientific studies and the usage of the drug began over 40 years ago. (Ref.)

In this time period, DCA has been constantly used as a medication for congenital mitochondrial diseases. The research done by Peter Stacpoole and his colleagues proved that when used for therapy, Sodium dichloroacetate can cause nonemild or moderate side effects. (Ref.)

The probability of adverse reactions is dependent on the dosing and the age of the patient. Larger DCA doses and  older patient age (above 40 years) are related to a higher side effect occurrence. (Ref.)

On exceptionally rare occasions, a small portion of the population can metabolize DCA more slowly than the average. For this reason, even the standard DCA doses can cause adverse reactions to appear faster and more prominent in this group of people. In this case, lowering the DCA dose should fix the issues.

If you stop taking DCA, almost all of the side effects disappear in less than a week. The reversible peripheral neuropathy can sometimes take up to 7 or 14 days (rarely) to resolve completely. (Ref.)

According to one of the most famous DCA clinics and their observational data, 44 % of the patients who have taken DCA did not experience side effects.

The most common side effects caused by Dichloroacetate:

▪ Peripheral neuropathy.
(experienced by up to 20% of people who use DCA).

This group of symptoms begins in the fingers, hands and feet. Depending on the intensity of the neuropathy, it can manifest as tingling, numbness, tremor, painful sensations and slightly increased difficulty of coordinated movement.
On less common occasions, neuropathy can emerge in other places and appear as the tingling of eyes, lips and tongue.

Typically, at least a couple of weeks or months are needed for peripheral neuropathy to develop.
This side effect is reversible – its intensity can decrease or it can disappear completely upon lowering the DCA dose or stopping DCA usage. (Ref.)

▪ Sleepiness, mental fogginess, confusion
(experienced by up to 20% of people who use DCA).

This group of symptoms is reversible – you can decrease their intensity or completely make them disappear by lowering the DCA dose or stopping DCA usage.

The rare side effects caused by Dichloroacetate:

▪ Heartburn, nausea, digestive disorders.

Administering Dichloroacetate through the mouth can sometimes cause GI irritability.

▪ Pain at the tumor site (temporary and then resolves).

A very rare adverse reaction. It indicates that due increased apoptosis a lot of cancer cells are dying and indicates that DCA therapy is effective. However, only a couple of Tumor lysis syndrome cases were documented in the most popular DCA administering clinics. This situation is more likely to happen to people who have leukemia, lymphoma or big volume tumors. (Ref.1Ref.2)

▪ Mild liver enzyme (AST, ALT, GGT) elevation, without symptoms.

A majority of medications can cause mild liver enzyme changes in the blood. DCA can cause minimal liver transaminase and transpeptidase elevations (about 50 – 60 U/l) for 1 % of the patients. These little alterations should not cause any worries.
A similar or bigger liver enzyme increase can be influenced by antibiotic, paracetamol (acetaminophen), some types of medicinal herbs and birth control pills. (Ref.)

▪ Increased anxiety, mood changes, hallucinations.

These effects are temporary and should disappear with the discontinued use of DCA. They are more likely to appear in patients that are using drugs which strongly influence the Central nervous system.

Dichloroacetate influence on different organ systems:

▪ DCA and the brain.
If you are currently using cannabinoids, benzodiazepines, opioids or other drugs which affect the Central nervous system, keep in mind that DCA can amplify the adverse reactions caused by these medications (eg. Delirium, memory problems).
This scenario is more likely to happen if the prescriptions have already caused side effects. If the patient is not experiencing any issues with the CNS affecting drugs – the risk for such interactions with DCA is low.

To minimize the probability of these drugs interacting, we recommend starting with low Sodium dichloroacetate doses and to gradually increase them. (Ref.)

▪ DCA and the heart.
Dichloroacetate seems to have a positive effect for the heart function without increasing the additional demand for oxygen. It also improves the efficiency of energy generation in the heart muscle. The drug is safe to use for people with heart failure and increased risk of cardiac ischemia. (Ref.)

▪ DCA and the liver.
In case of liver failure and severe jaundice don’t use high doses of DCA because Dichloroacetate is metabolised in the liver. In situations like these, DCA should be administered intravenously and not through the mouth. (Ref.)

▪ DCA and the kidneys.
Dichloroacetate is safe for patients who have kidney failure. The drug has no toxicity for the kidneys.

▪ DCA and diabetes.
Patients who have diabetes can achieve better blood glycemic control with the help of Sodium Dichloroacetate. DCA seems to lower the blood sugar in between meals. (Ref.)

This is the current accurate information on how DCA affects the major organs in the body. We can come to a conclusion that if Sodium Dichloroacetate is administered with care and adequate basic knowledge, its health risks are low and can be almost entirely prevented.

We hope this article answers the most important questions.

How DCA Works

For almost half a century, DCA has been a relatively basic substance used for treating people with congenital mitochondrial diseases. Nearly a decade ago, the interest in this drug spiked up because of new research and claims that it could be able to serve those who have cancer. Since then, there has been a lot of interest generated towards this medication.

In this long article, we will attempt to briefly cover what we know about dichloroacetate and how it works. Keep in mind – we‘ll try to explain the complex mechanisms as simply as possible. We encourage every person interested in DCA therapy to read on.

So… How does a small, inexpensive and a relatively nontoxic molecule like dichloroacetate work ?

How cancer cells act differently ?

To better understand the mechanism of DCA, we must be aware of the different processes that thrive in a cancerous cell. Cancer is considered to be a genetic disease in which genes that control how our cells grow and divide start behaving abnormally. Due to error in our DNA, the cells become chaotic, multiply uncontrollably and change their normal metabolic activity.

Every cell contains important organelles called mitochondria. These structures can be called “cellular power plants” because they produce the energy needed for live organisms to function properly. Besides, mitochondria are important in the cells life cycle – they play key roles in activating apoptosis.

Unfortunately, cancer cells have reduced mitochondrial function. This means that cancerous cells mostly produce energy by extremely high rates of glycolysis outside the mitochondria, rather than oxidative phosphorylation inside the mitochondria (Warburg effect) which also causes a massive increase in uptake of glucose and the exhaustion of the patient.

Because of the intracellular metabolic changes apoptosis (natural cell death) is stopped and it makes the malignant cells “immortal”.

Suppressed mitochondrion function leads to a lot of advantages for the tumor – it can survive and grow without oxygen in anaerobic conditions (eg. the cells in the middle of a cancerous mass), it promotes biosynthesis (cancer growth and division), it evades immune cells and disrupts the normal architecture of tissues (the cancer becomes more malignant and dangerous).

On the top of that, the Warburg effect produces an acidic environment. Such conditions damage the intercellular matrix, set the cancerous cells free into the bloodstream or lymph and promote metastasis (the cancer can spread and become deadly).

As we can see, the Warburg effect causes metabolic changes that make cancer a hardly manageable illness. Nevertheless, recently there have been ideas to begin perceiving and approaching cancer as a metabolic disease and this is where the molecule of DCA comes in handy.

How DCA affects cancer ?

So far we can understand how the cellular metabolism of tumors differs from that of our healthy, normal cells. Malignant cells switch off their mitochondria and start producing energy mainly through cytoplasmic glycolysis and these changes generate a lot of advantages for the tumor.

Dichloroacetate works by restoring the suppressed mitochondrial function and rendering the “bad cells” non cancerous. The normalized mitochondria then are able to resume the halted apoptosis process (the natural intracellular suicide system) and the harmful cells start dying on their own. What’s more important, the drug is selective. It doesn’t poison healthy tissues and cause significant effects on non carcinogenic cells like cytotoxic chemotherapy drugs.

The way DCA achieves these results is by reversing the Warburg effect. The substance inhibits an important enzyme which is essential for cancer proliferation – pyruvate dehydrogenase kinase (PDK). Once again the cell starts producing most of its energy in a normal way (through oxidative phosphorylation). The mechanism restores normal cellular metabolic activity.

Notably, Sodium Dichloroacetate has a lot of characteristics of an ideal antitumor therapy. We will discuss these characteristics further.

Why DCA is a good anticancer medication ?

To begin with, as a result of increased apoptosis, the substance effectively stops tumor growth (proliferation) and can even cause them to shrink in size or disappear.

To our surprise, DCA can also reduce the vascularity of tumors (by inhibiting angiogenesis). This prevents the nutrients from reaching and feeding the “bad cells”. Less blood vessel deposition on the cancerous masses also means that there are fewer pathways for cancer to spread – this lowers the probability of metastasis and disease progression.

Last but not least, since dichloroacetate is a small molecule, it crosses the blood-brain barrier and can help manage brain tumors. Currently, there are only few prescriptions that can reach the cerebral matter, making DCA a considerable option for therapy.

However, we are used to the reality that anticancer medications cause severe outcomes. Chemotherapy can have a very harsh effect on the body and provide unpleasant experiences. This is why patients are specifically prepared and receive medications prior to the administration of chemotherapy, to help minimize this

Despite that, DCA isn’t considered to be a cytotoxic chemotherapy drug and it appears to cause minimal systemic toxicity. Dichloroacetate is a gentle non-chemo treatment option that can have none, little or mild side reactions.

Then again, all the side effects are reversible which makes it the most appealing characteristic of using this molecule.

To put in simply, DCA induces intracellular as well as macroscopic changes that can help you accomplish successful therapy against cancer and achieve good improvements. Many people start feeling better in weeks.

What positive improvements people can expect ?

Given the fact that now we understand enough things about this relatively new cancer treatment,  we can turn our attention from a scientific perspective to a more practical point of view. What are the possible experiences when using Sodium Dichloroacetate ?

Bare in mind that the information we present is based on real and open observational data gathered from the clinical practise of top DCA therapy centers in the world. We must remember the main point which is true to every cancer case there is – the earlier the disease is caught and diagnosed, the sooner we take action, the better results we will achieve. The DCA treatment will not always provide positive outcomes and help everyone.

The lowest positive response is disease stabilization. This means that the tumor stops spreading and growing. There are no further signs of cancer progression.

As a result of taking DCA, a much better positive response can be improved symptoms. Patients regain their appetite, feel more energized, reduce their fatigue, regain weight and feel less pain. These things tend to last for a sustained period of time.

More importantly, people suffering from cancer obtain an improvement in blood tests and a reduction of tumor markers.

The best results of using DCA are measurable tumour size reduction or complete cancer remission. DCA users have their tumours screened by imaging techniques such as CT scans,  Magnetic resonance imaging, Ultrasonography and report significant cancer size reduction. Some of them even report complete cancer recovery.

Half of the people who take DCA experience mild side effects that most of the time are neurological and can be improved by a couple of dietary supplements (eg. Vitamin B1Alpha-Lipoic Acid)  or by taking a break from the treatment.

When all the things are considered, we must emphasize that sodium dichloroacetate can be taken alone or in combination with other anticancer medications. Naturally, a lot of people are eager to know – is DCA acceptable with other forms of cancer therapy ?

In short – yes. It is possible and even encouraged (with a couple of exceptions).

New DCA Publication!

TITLE Long-term stabilization of metastatic melanoma with sodium dichloroacetate
AUTHOR(s) Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn
CITATION Khan A, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017; 8(4): 371-377
URL http://www.wjgnet.com/2218-4333/full/v8/i4/371.htm
DOI http://dx.doi.org/10.5306/wjco.v8.i4.371
OPEN ACCESS This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
CORE TIP Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007. It has been shown that DCA therapy can result in a classic response which is measured by reduction or disappearance of tumours on imaging. However, DCA can also halt cancer cell growth without causing apoptosis (cytostatic effect). This can result in long-term stabilization of metastatic cancer. We present a case of oral DCA therapy resulting in reduction and stabilization of metastatic melanoma in a 32-year-old male for over 4 years, with only minor side effects.
KEY WORDS Dichloroacetate; Cancer; BRAF; Melanoma; Cytostatic
COPYRIGHT © The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
NAME OF JOURNAL World Journal of Clinical Oncology
ISSN 2218-4333
PUBLISHER Baishideng Publishing Group Inc, 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA
WEBSITE Http://www.wjgnet.com

CASE REPORT

 

Long-term stabilization of metastatic melanoma with sodium dichloroacetate

 

Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn

 

Akbar Khan, Doug Andrews, Medicor Cancer Centres Inc, Toronto, ON M2N 6N4, Canada

Jill Shainhouse, Insight Naturopathic Clinic, Toronto, ON M4P 1N9, Canada

Anneke C Blackburn, the John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia

Author contributions: Khan A treated the patient and wrote most of the case report; Andrews D assisted in development of the natural medication protocol for reduction of DCA side effects, and wrote a portion of the case report; Shainhouse J treated the patient with natural therapy; Blackburn AC interpreted the case report in the context of the literature on in vitro and in vivo DCA research, wrote parts of the introduction and discussion, and reviewed the manuscript overall.

Correspondence to: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc, 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada. akhan@medicorcancer.com

Telephone: +1-416-2270037  Fax: +1-416-2271915

Received: January 30, 2017   Revised: May 5, 2017   Accepted: May 30, 2017

Published online: August 10, 2017

 

Abstract

Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a pub­lication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the res­ponse of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of re­current metastatic melanoma for over 4 years’ duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain long-term stability in patients with advanced melanoma.

 

Key words: Dichloroacetate; Cancer; BRAF; Melanoma; Cytostatic

 

Khan A, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017; 8(4): 371-377  Available from: URL: http://www.wjgnet.com/2218-4333/full/v8/i4/371.htm  DOI: http://dx.doi.org/10.5306/wjco.v8.i4.371

 

Core tip: Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007. It has been shown that DCA therapy can result in a classic response which is measured by reduction or disappearance of tumours on imaging. However, DCA can also halt cancer cell growth without causing apoptosis (cytostatic effect). This can result in long-term stabilization of metastatic cancer. We present a case of oral DCA therapy resulting in reduction and stabilization of metastatic melanoma in a 32-year-old male for over 4 years, with only minor side effects.

 

INTRODUCTION

Sodium dichloroacetate (DCA) caught the attention of the medical community in 2007, when Bonnet et al[1] published the first in vitro and in vivo study illustrating the value of DCA as a metabolic cancer therapy, through its inhibitory action on the mitochondrial enzyme py­ruvate dehydrogenase kinase. Previously, Stacpoole et al[2-4] had published several studies of DCA for the treatment of congenital lactic acidosis in mitochondrial diseases[2-5]. These studies demonstrated that oral DCA is a safe drug for human use. DCA was noted to have an absence of renal, pulmonary, bone marrow and cardiac toxicity[4]. Most DCA side effects were modest, with the most serious one being reversible peripheral neuropathy[6]. Reversible delirium has also been reported[7]. Elevation of liver enzymes (asymptomatic and reversible) has been noted in a small percentage of patients[3]. The prior human research in mitochondrial disorders has enabled the rapid translation of DCA into human use as an off-label cancer therapy. Several reports of clinical trials using DCA as cancer therapy have now been published, confirming its safety profile, and indicating an increasing recognition of the potential usefulness of DCA in the cancer clinic[8-11]. One limitation of these studies involving late stage patients is that they have only reported on treatment for short periods of time.

In Bonnet’s 2007 publication[1], DCA treatment was shown to reduce mitochondrial membrane potential which promoted apoptosis selectively in human cancer cells. Aerobic glycolysis inhibition (the Warburg effect) and mitochondrial potassium ion channel activation were identified as the mechanisms of action of DCA. Further investigations of DCA in vitro have confirmed the anti-cancer activity against a wide range of can­cer types, which have been reviewed recently by Kankotia and Stacpoole[12]. In addition, DCA is also able to enhance apoptosis when combined with other agents[13-15]. Other anticancer actions of DCA have also been suggested, including angiogenesis inhibition[16], alteration of HIF1-a expression[17], alteration of cell pH regulators V-ATPase and MCT1, and other cell survival regulators such as p53 and PUMA[18]. However, many in vitro studies use unreasonably high concentrations of DCA that are not clinically achievable, in an effort to show cytotoxic activity[12]. In other studies, more modest DCA concentrations were used, demonstrating that DCA could be cytostatic. The second report in 2010 of its in vivo anti-cancer activity found DCA alone to be cytostatic in a metastatic model of breast cancer[19], inhibiting proliferation without triggering apoptosis. This suggests a role for DCA as a cancer stabilizer, similar to angiogenesis inhibitors.

In response to the 2007 report of the anti-cancer actions of DCA, Khan began using DCA for the treat­ment of cancer patients with short prognosis or who had stopped responding to conventional cancer therapies. A natural medication protocol was developed in collaboration with a naturopathic physician (Andrews) to address the dose-limiting neurologic toxicity of DCA. This consisted of 3 medicines: Acetyl L-carnitine[20-22], R-alpha lipoic acid[23-25] and benfotiamine[26-28], for neuropathy and encephalopathy prevention. In over 300 advanced stage cancer patients, observational data revealed that DCA therapy benefitted 60%-70% of cases. The neuropathy risk when natural neuro­protective medicines were combined with DCA was approximately 20% using 20-25 mg/kg per day dosing on a 2 wk on/1 wk off cycle (clinic observational data published online at www.medicorcancer.com). Here, a patient case report illustrating both the apoptotic and anti-proliferative effects of chronic DCA treatment over a period of over four years is presented.

 

CASE REPORT

A 32 years old previously healthy fair-skinned male originally noted that a mole on his left calf began to change in 2006. He consulted a doctor and the mole was excised. A pathologic diagnosis of melanoma was made. A sentinel node dissection was carried out, and was negative for metastatic disease. In 2007, the patient noted enlargement of left inguinal lymph nodes, and small melanocytic lesions on the skin of his left leg. He was treated with interferon alpha under a clinical trial at a regional cancer hospital, with reduction of the nodes and resolution of the skin metastases. Interferon was stopped after 9 mo due to side effects.

The patient remained well until 2010, when a new left leg skin metastasis appeared. This was surgically excised. In late 2011, another new cutaneous meta­stasis was identified on the left leg, within the scar from the original melanoma surgery. This was biopsied and a diagnosis of recurrent melanoma was confirmed. He was then treated with wide excision and skin graft.

In March 2012, the patient was diagnosed with a recurrence within the left leg skin graft. This was excised and a new skin graft procedure was performed. Pathology revealed positive margins of the excised metastasis, so a re-excision was performed, again with positive margins. At the same time, needle biopsy of a left inguinal lymph node confirmed the presence of BRAF-positive metastatic melanoma. A Computed tomography (CT) scan performed in Mar 2012 revealed no evidence of distant metastases. The largest left inguinal node was 8mm in diameter, which was reported as “insignificant by size criteria” (Figure 1).

In April 2012, the patient consulted a naturopathic doctor (Shainhouse) and began therapy with the following oral natural anti-cancer agents: Active hexose correlated compound or AHCC (mushroom extract)[29], dandelion root[30], curcumin[31], and astragalus root[32]. Parenteral therapy was also started, which consisted of intravenous vitamin C twice weekly[33] and subcutaneous European mistletoe extract[34]. The patient also changed to a vegan diet.

In May 2012, the patient attended the author’s clinic (Khan) looking to pursue additional non-traditional therapies. DCA therapy was discussed, but the patient decided to give the natural anti-cancer therapies (pre­scribed by Shainhouse) an adequate trial first. CT scan was performed again in May 2012 (after only 1 mo of natural therapy) and indicated mild growth of multiple inguinal and external iliac nodes, with sizes ranging from 10 mm × 11 mm to 14 mm × 15 mm.

In July 2012, CT scan was repeated to assess the patient’s natural anti-cancer therapies. At that time, the left inguinal and external iliac nodes had enlarged again, and ranged in size from 13 mm × 16 mm to 22 mm × 20 mm (Figure 2). PET scan was also performed in preparation for entering a clinical trial in Boston, MA (United States), and confirmed increased glucose uptake in the left inguinal nodes. There was new low intensity (2/10) aching pain in the left inguinal region. Examination revealed a 20 mm non-tender left inguinal lymph node, and two small skin metastases within the left calf skin graft.

The patient was thus diagnosed with disease progression. At that point he decided to initiate DCA therapy. He began oral DCA 500 mg 3 times per day, which was equivalent to 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States) in addition to maintaining the other natural therapies. The DCA treatment cycle was 2 wk on and 1 wk off. To minimize the occurrence of DCA side effects, 3 additional natural medications were prescribed: Oral acetyl L-carnitine 500 mg 3 times a day, oral benfotiamine 80 mg twice a day and oral R-alpha lipoic acid 150 mg 3 times a day. These supplements were taken daily (no cycle). Routine baseline blood tests were performed (Table 1). These were all normal, except for low creatinine which was felt to be insignificant.

In November 2012, 4 mo after the addition of DCA to his original natural anti-cancer therapies, the patient was re-assessed. He felt generally well. Two new symptoms were reported to have begun only after initiation of DCA therapy: Slightly reduced sensation of the finger tips and toes, and slightly reduced ability to concentrate during the 2 wk periods in which he was taking DCA. The mild sensory loss was not worsening and was felt to be mild DCA-related neuropathy. Both the numbness and reduced concentration were reported to resolve during the weeks when the patient was off DCA. Blood panel from October 2012 showed no significant changes (Table 1). August 2012 and November 2012 CT scans revealed significant regression of all previously enlarged lymph nodes. The largest node was 10 mm, and there was no evidence of intra-thoracic or intra-abdominal disease, and no bone metastases (Figure 3).

The patient continued to feel well on DCA therapy, and did not notice any new skin metastases or new enlargement of inguinal nodes. He continued to have frequent clinical monitoring with his naturopathic doctor (Shainhouse), and annual follow-up with his medical doctor (Khan). The listed natural anti-cancer therapies (prescribed by Shainhouse) and DCA therapy were maintained into 2016. Blood panel results in June 2016 continued to be normal (Table 1). CT scan was repeated in August 2016, showing no evidence of metastatic melanoma, after a full 4 years of ongoing DCA therapy, combined with natural anti-cancer therapy (Figure 4). By December 2016, the patient reported an increase in work-related stress and a reduction in compliance with his medications. At the time, he noted a new left inguinal mass. Ultrasound imaging was obtained, which revealed a new conglomerate of enlarged lymph nodes measuring 40 mm × 25 mm × 23 mm, with colour Doppler showing blood flow within the mass. This was interpreted as re-growth of melanoma, after approximately four and a half years of continuous DCA therapy. Further workup was performed including a PET/CT scan, which confirmed disease recurrence in 3 left inguinal nodes (SUVmax ranging from 13 to 17.8).

In summary, the patient received conventional therapy for recurrent stage 3 melanoma over a period of 6 years, consisting of primary surgical excision with lymph node dissection, interferon alpha and surgical excisions for recurrent cutaneous metastases on 5 occasions. The patient then received natural anti-cancer therapy alone (prescribed by Shainhouse) for 3 mo with no response, evidenced by steady disease progression on serial CT scans. Finally the patient added oral DCA therapy to the natural anti-cancer therapy, with 3 concurrent neuroprotective medicines (lipoic acid, acetyl L-carnitine and benfotiamine) and no concurrent conventional cancer therapies. The result was a complete radiological remission lasting for over 4 years, followed by recurrence. During the course of DCA therapy, the patient experienced trivial side effects consisting of slight neuropathy and slight reduction of concentration. The patient maintained ECOG level 0 function, and he was able to work full time.

 

DISCUSSION

The use of oral DCA in the metastatic melanoma patient described herein demonstrates tumour shrinkage and long-term disease stability according to clinical status and CT imaging. Disease stability was maintained for over 4 years while taking DCA in the absence of any concurrent conventional therapy, with a survival time since the initial diagnosis of 10 years. According to the National Cancer Institute’s SEER cancer statistics, the survival of this patient who showed no evidence of distant metastases is not remarkable (62.9% 5-year survival rate for melanoma with spread to regional lymph nodes, https://seer.cancer.gov/statfacts/html/melan.html). What is remarkable is that in a situation where involved lymph nodes were clearly enlarging, the addition of oral DCA therapy was efficacious in shrinking the enlarging nodes (Figures 2 and 3), and in achieving a remission lasting over 4 years. It is possible that the natural anti-cancer therapies the patient received synergized with DCA, but it is also clear that these natural therapies alone cannot account for the disease regression. DCA has been reported to have both apoptotic and cytostatic effects[14,17,19,35,36], which is consistent with this patient’s clinical course of regression (apoptotic) and prolonged remission (cytostatic). The recurrence after 4 years coincided with reduced compliance, suggesting that this method of cancer management with DCA requires the metabolic pressure to be maintained continuously. Despite recurrence, the patient remained clinically well and planned to start new immunotherapy medications. It remains to be seen if a change in therapy can once again achieve disease regression or stability.

In addition to the maintenance of remission for over 4 years, this case illustrates that DCA can be well-tolerated in a cancer patient for a prolonged time period, as compared to all published DCA cancer clinical trials. Notably, this patient was able to tolerate 17 mg/kg per day in a regime of 2 wk on/1 wk off for 4 years with minimal side effects. This is similar to our previous case report of chronic DCA usage in colon cancer[37], where the patient was able to tolerate 16 mg/kg per day (but not 25 mg/kg per day) in the same regime, but contrasts with the clinical trials for DCA, which recommend a lower dose of 10-12.5 mg/kg per day given continuously[9,11]. The 1 wk break or the neuroprotective supplements may both contribute to the ability of the patients in the case reports to tolerate the higher dose. Genetic polymorphisms in GSTZ1, the liver enzyme that metabolises DCA, may also contribute to the dose of DCA that can be tolerated[9,38]. Variable drug levels have been reported in the trials, but not all of them have considered this pharmacogenetic aspect of DCA therapy[9,11], and further studies are needed to clarify if this is a significant contributor to DCA tolerance. As of this writing, a DCA multiple myeloma human trial is ongoing, which is examining both GSTZ1 genotypes and drug levels to contribute to our understanding of these issues (Australia New Zealand Clinical Trials Register #ACTRN12615000226505, http://www.anzctr.org.au).

This case report shows that chronic DCA therapy can be used without reducing quality of life, as compared to conventional melanoma therapies such as interferon. To determine the optimal protocol for maximum tolerable acute or chronic treatment with DCA, human trials are needed. But more importantly, it still remains to be clarified what dose is required for on-target effects that will be efficacious against cancer. This information is necessary before investing in larger, long term studies on patient outcomes. DCA deserves further investigation in clinical trials as a non-toxic cancer therapy due to its modest cost and low toxicity, and deserves consideration as an off-label cancer therapy.

 

ACKNOWLEDGMENTS

The authors wish to thank Dr. Humaira Khan for her assistance, and also the patient for his support and consent to publish his case.

 

COMMENTS

Case characteristics

The 32-year-old male patient presented with a pigmented lesion on his leg.

 

Clinical diagnosis

The patient was diagnosed with a melanoma.

 

Laboratory diagnosis

Melanoma confirmed by excisional biopsy.

 

Imaging diagnosis

Enlarged inguinal node confirmed to be involved with melanoma (needle biopsy).

 

Pathological diagnosis

Melanoma, BRAF positive.

 

Treatment

Excision of primary lesion with skin graft, sentinel node dissection, multiple excisions of recurrent cutaneous metastases. Traditional therapy stopped and natural anti-cancer therapies started (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). Progression after 3 mo, dichloroacetate (DCA) added. Regression and remission following addition of DCA lasting for over 4 years.

 

Related reports

Computed tomography scan reports demonstrate the course of the disease and response to therapies.

 

Term explanation

DCA: Dichloroacetate sodium; RECIST: Response Evaluation Criteria for Solid Tumours; ECOG: Eastern Cooperative Oncology Group.

 

Experiences and lessons

DCA can act as a pro-apoptotic and cytostatic drug, and can thus achieve regression as well as long-term stabilization of metastatic cancer without serious side effects, as illustrated by this melanoma case.

 

Peer-review

Dr. Khan described a 32-year-old man received DCA therapy, with other medications from natural therapists and maintained in a stabilization state (metastatic melanoma) for over 4 years. It is an interesting case.

 

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FIGURE LEGENDS

Figure 1  Computed tomography scan from March 2012 prior to natural therapies and prior to dichloroacetate therapy. Largest node measured 8 mm in diameter.

Figure 2  Computed tomography scan from July 2012 after 3 mo of natural therapy alone, just prior to the start of dichloroacetate therapy. Largest node measured 22 mm × 20 mm.

Figure 3  Computed tomography scan from November 2012 after 4 mo of dichloroacetate therapy. Largest node measured 10 mm.

Figure 4  Computed tomography scan after 4 years of dichloroacetate therapy without any concurrent conventional cancer therapies. Scan demonstrates absence of cancer re-growth. All nodes measure less than 10 mm.

 

FOOTNOTES

Informed consent statement: The patient described in this manuscript has given consent to publish his case anonymously.

Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invited manuscript

Peer-review started: February 12, 2017

First decision: March 28, 2017

Article in press: May 31, 2017

P- Reviewer: Su CC    S- Editor: Ji FF    L- Editor: A    E- Editor: Lu YJ 

 

 

 

 

 

 

 

 

 

 

 

 

CASE REPORT

 

Long-term stabilization of metastatic melanoma with sodium dichloroacetate

 

Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn

 

Akbar Khan, Doug Andrews, Medicor Cancer Centres Inc, Toronto, ON M2N 6N4, Canada

Jill Shainhouse, Insight Naturopathic Clinic, Toronto, ON M4P 1N9, Canada

Anneke C Blackburn, the John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia

Author contributions: Khan A treated the patient and wrote most of the case report; Andrews D assisted in development of the natural medication protocol for reduction of DCA side effects, and wrote a portion of the case report; Shainhouse J treated the patient with natural therapy; Blackburn AC interpreted the case report in the context of the literature on in vitro and in vivo DCA research, wrote parts of the introduction and discussion, and reviewed the manuscript overall.

Correspondence to: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc, 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada. akhan@medicorcancer.com

Telephone: +1-416-2270037  Fax: +1-416-2271915

Received: January 30, 2017   Revised: May 5, 2017   Accepted: May 30, 2017

Published online: August 10, 2017

 

Abstract

Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a pub­lication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the res­ponse of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of re­current metastatic melanoma for over 4 years’ duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain long-term stability in patients with advanced melanoma.

 

Key words: Dichloroacetate; Cancer; BRAF; Melanoma; Cytostatic

 

Khan A, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017; 8(4): 371-377  Available from: URL: http://www.wjgnet.com/2218-4333/full/v8/i4/371.htm  DOI: http://dx.doi.org/10.5306/wjco.v8.i4.371

 

Core tip: Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007. It has been shown that DCA therapy can result in a classic response which is measured by reduction or disappearance of tumours on imaging. However, DCA can also halt cancer cell growth without causing apoptosis (cytostatic effect). This can result in long-term stabilization of metastatic cancer. We present a case of oral DCA therapy resulting in reduction and stabilization of metastatic melanoma in a 32-year-old male for over 4 years, with only minor side effects.

 

INTRODUCTION

Sodium dichloroacetate (DCA) caught the attention of the medical community in 2007, when Bonnet et al[1] published the first in vitro and in vivo study illustrating the value of DCA as a metabolic cancer therapy, through its inhibitory action on the mitochondrial enzyme py­ruvate dehydrogenase kinase. Previously, Stacpoole et al[2-4] had published several studies of DCA for the treatment of congenital lactic acidosis in mitochondrial diseases[2-5]. These studies demonstrated that oral DCA is a safe drug for human use. DCA was noted to have an absence of renal, pulmonary, bone marrow and cardiac toxicity[4]. Most DCA side effects were modest, with the most serious one being reversible peripheral neuropathy[6]. Reversible delirium has also been reported[7]. Elevation of liver enzymes (asymptomatic and reversible) has been noted in a small percentage of patients[3]. The prior human research in mitochondrial disorders has enabled the rapid translation of DCA into human use as an off-label cancer therapy. Several reports of clinical trials using DCA as cancer therapy have now been published, confirming its safety profile, and indicating an increasing recognition of the potential usefulness of DCA in the cancer clinic[8-11]. One limitation of these studies involving late stage patients is that they have only reported on treatment for short periods of time.

In Bonnet’s 2007 publication[1], DCA treatment was shown to reduce mitochondrial membrane potential which promoted apoptosis selectively in human cancer cells. Aerobic glycolysis inhibition (the Warburg effect) and mitochondrial potassium ion channel activation were identified as the mechanisms of action of DCA. Further investigations of DCA in vitro have confirmed the anti-cancer activity against a wide range of can­cer types, which have been reviewed recently by Kankotia and Stacpoole[12]. In addition, DCA is also able to enhance apoptosis when combined with other agents[13-15]. Other anticancer actions of DCA have also been suggested, including angiogenesis inhibition[16], alteration of HIF1-a expression[17], alteration of cell pH regulators V-ATPase and MCT1, and other cell survival regulators such as p53 and PUMA[18]. However, many in vitro studies use unreasonably high concentrations of DCA that are not clinically achievable, in an effort to show cytotoxic activity[12]. In other studies, more modest DCA concentrations were used, demonstrating that DCA could be cytostatic. The second report in 2010 of its in vivo anti-cancer activity found DCA alone to be cytostatic in a metastatic model of breast cancer[19], inhibiting proliferation without triggering apoptosis. This suggests a role for DCA as a cancer stabilizer, similar to angiogenesis inhibitors.

In response to the 2007 report of the anti-cancer actions of DCA, Khan began using DCA for the treat­ment of cancer patients with short prognosis or who had stopped responding to conventional cancer therapies. A natural medication protocol was developed in collaboration with a naturopathic physician (Andrews) to address the dose-limiting neurologic toxicity of DCA. This consisted of 3 medicines: Acetyl L-carnitine[20-22], R-alpha lipoic acid[23-25] and benfotiamine[26-28], for neuropathy and encephalopathy prevention. In over 300 advanced stage cancer patients, observational data revealed that DCA therapy benefitted 60%-70% of cases. The neuropathy risk when natural neuro­protective medicines were combined with DCA was approximately 20% using 20-25 mg/kg per day dosing on a 2 wk on/1 wk off cycle (clinic observational data published online at www.medicorcancer.com). Here, a patient case report illustrating both the apoptotic and anti-proliferative effects of chronic DCA treatment over a period of over four years is presented.

 

CASE REPORT

A 32 years old previously healthy fair-skinned male originally noted that a mole on his left calf began to change in 2006. He consulted a doctor and the mole was excised. A pathologic diagnosis of melanoma was made. A sentinel node dissection was carried out, and was negative for metastatic disease. In 2007, the patient noted enlargement of left inguinal lymph nodes, and small melanocytic lesions on the skin of his left leg. He was treated with interferon alpha under a clinical trial at a regional cancer hospital, with reduction of the nodes and resolution of the skin metastases. Interferon was stopped after 9 mo due to side effects.

The patient remained well until 2010, when a new left leg skin metastasis appeared. This was surgically excised. In late 2011, another new cutaneous meta­stasis was identified on the left leg, within the scar from the original melanoma surgery. This was biopsied and a diagnosis of recurrent melanoma was confirmed. He was then treated with wide excision and skin graft.

In March 2012, the patient was diagnosed with a recurrence within the left leg skin graft. This was excised and a new skin graft procedure was performed. Pathology revealed positive margins of the excised metastasis, so a re-excision was performed, again with positive margins. At the same time, needle biopsy of a left inguinal lymph node confirmed the presence of BRAF-positive metastatic melanoma. A Computed tomography (CT) scan performed in Mar 2012 revealed no evidence of distant metastases. The largest left inguinal node was 8mm in diameter, which was reported as “insignificant by size criteria” (Figure 1).

In April 2012, the patient consulted a naturopathic doctor (Shainhouse) and began therapy with the following oral natural anti-cancer agents: Active hexose correlated compound or AHCC (mushroom extract)[29], dandelion root[30], curcumin[31], and astragalus root[32]. Parenteral therapy was also started, which consisted of intravenous vitamin C twice weekly[33] and subcutaneous European mistletoe extract[34]. The patient also changed to a vegan diet.

In May 2012, the patient attended the author’s clinic (Khan) looking to pursue additional non-traditional therapies. DCA therapy was discussed, but the patient decided to give the natural anti-cancer therapies (pre­scribed by Shainhouse) an adequate trial first. CT scan was performed again in May 2012 (after only 1 mo of natural therapy) and indicated mild growth of multiple inguinal and external iliac nodes, with sizes ranging from 10 mm × 11 mm to 14 mm × 15 mm.

In July 2012, CT scan was repeated to assess the patient’s natural anti-cancer therapies. At that time, the left inguinal and external iliac nodes had enlarged again, and ranged in size from 13 mm × 16 mm to 22 mm × 20 mm (Figure 2). PET scan was also performed in preparation for entering a clinical trial in Boston, MA (United States), and confirmed increased glucose uptake in the left inguinal nodes. There was new low intensity (2/10) aching pain in the left inguinal region. Examination revealed a 20 mm non-tender left inguinal lymph node, and two small skin metastases within the left calf skin graft.

The patient was thus diagnosed with disease progression. At that point he decided to initiate DCA therapy. He began oral DCA 500 mg 3 times per day, which was equivalent to 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States) in addition to maintaining the other natural therapies. The DCA treatment cycle was 2 wk on and 1 wk off. To minimize the occurrence of DCA side effects, 3 additional natural medications were prescribed: Oral acetyl L-carnitine 500 mg 3 times a day, oral benfotiamine 80 mg twice a day and oral R-alpha lipoic acid 150 mg 3 times a day. These supplements were taken daily (no cycle). Routine baseline blood tests were performed (Table 1). These were all normal, except for low creatinine which was felt to be insignificant.

In November 2012, 4 mo after the addition of DCA to his original natural anti-cancer therapies, the patient was re-assessed. He felt generally well. Two new symptoms were reported to have begun only after initiation of DCA therapy: Slightly reduced sensation of the finger tips and toes, and slightly reduced ability to concentrate during the 2 wk periods in which he was taking DCA. The mild sensory loss was not worsening and was felt to be mild DCA-related neuropathy. Both the numbness and reduced concentration were reported to resolve during the weeks when the patient was off DCA. Blood panel from October 2012 showed no significant changes (Table 1). August 2012 and November 2012 CT scans revealed significant regression of all previously enlarged lymph nodes. The largest node was 10 mm, and there was no evidence of intra-thoracic or intra-abdominal disease, and no bone metastases (Figure 3).

The patient continued to feel well on DCA therapy, and did not notice any new skin metastases or new enlargement of inguinal nodes. He continued to have frequent clinical monitoring with his naturopathic doctor (Shainhouse), and annual follow-up with his medical doctor (Khan). The listed natural anti-cancer therapies (prescribed by Shainhouse) and DCA therapy were maintained into 2016. Blood panel results in June 2016 continued to be normal (Table 1). CT scan was repeated in August 2016, showing no evidence of metastatic melanoma, after a full 4 years of ongoing DCA therapy, combined with natural anti-cancer therapy (Figure 4). By December 2016, the patient reported an increase in work-related stress and a reduction in compliance with his medications. At the time, he noted a new left inguinal mass. Ultrasound imaging was obtained, which revealed a new conglomerate of enlarged lymph nodes measuring 40 mm × 25 mm × 23 mm, with colour Doppler showing blood flow within the mass. This was interpreted as re-growth of melanoma, after approximately four and a half years of continuous DCA therapy. Further workup was performed including a PET/CT scan, which confirmed disease recurrence in 3 left inguinal nodes (SUVmax ranging from 13 to 17.8).

In summary, the patient received conventional therapy for recurrent stage 3 melanoma over a period of 6 years, consisting of primary surgical excision with lymph node dissection, interferon alpha and surgical excisions for recurrent cutaneous metastases on 5 occasions. The patient then received natural anti-cancer therapy alone (prescribed by Shainhouse) for 3 mo with no response, evidenced by steady disease progression on serial CT scans. Finally the patient added oral DCA therapy to the natural anti-cancer therapy, with 3 concurrent neuroprotective medicines (lipoic acid, acetyl L-carnitine and benfotiamine) and no concurrent conventional cancer therapies. The result was a complete radiological remission lasting for over 4 years, followed by recurrence. During the course of DCA therapy, the patient experienced trivial side effects consisting of slight neuropathy and slight reduction of concentration. The patient maintained ECOG level 0 function, and he was able to work full time.

 

DISCUSSION

The use of oral DCA in the metastatic melanoma patient described herein demonstrates tumour shrinkage and long-term disease stability according to clinical status and CT imaging. Disease stability was maintained for over 4 years while taking DCA in the absence of any concurrent conventional therapy, with a survival time since the initial diagnosis of 10 years. According to the National Cancer Institute’s SEER cancer statistics, the survival of this patient who showed no evidence of distant metastases is not remarkable (62.9% 5-year survival rate for melanoma with spread to regional lymph nodes, https://seer.cancer.gov/statfacts/html/melan.html). What is remarkable is that in a situation where involved lymph nodes were clearly enlarging, the addition of oral DCA therapy was efficacious in shrinking the enlarging nodes (Figures 2 and 3), and in achieving a remission lasting over 4 years. It is possible that the natural anti-cancer therapies the patient received synergized with DCA, but it is also clear that these natural therapies alone cannot account for the disease regression. DCA has been reported to have both apoptotic and cytostatic effects[14,17,19,35,36], which is consistent with this patient’s clinical course of regression (apoptotic) and prolonged remission (cytostatic). The recurrence after 4 years coincided with reduced compliance, suggesting that this method of cancer management with DCA requires the metabolic pressure to be maintained continuously. Despite recurrence, the patient remained clinically well and planned to start new immunotherapy medications. It remains to be seen if a change in therapy can once again achieve disease regression or stability.

In addition to the maintenance of remission for over 4 years, this case illustrates that DCA can be well-tolerated in a cancer patient for a prolonged time period, as compared to all published DCA cancer clinical trials. Notably, this patient was able to tolerate 17 mg/kg per day in a regime of 2 wk on/1 wk off for 4 years with minimal side effects. This is similar to our previous case report of chronic DCA usage in colon cancer[37], where the patient was able to tolerate 16 mg/kg per day (but not 25 mg/kg per day) in the same regime, but contrasts with the clinical trials for DCA, which recommend a lower dose of 10-12.5 mg/kg per day given continuously[9,11]. The 1 wk break or the neuroprotective supplements may both contribute to the ability of the patients in the case reports to tolerate the higher dose. Genetic polymorphisms in GSTZ1, the liver enzyme that metabolises DCA, may also contribute to the dose of DCA that can be tolerated[9,38]. Variable drug levels have been reported in the trials, but not all of them have considered this pharmacogenetic aspect of DCA therapy[9,11], and further studies are needed to clarify if this is a significant contributor to DCA tolerance. As of this writing, a DCA multiple myeloma human trial is ongoing, which is examining both GSTZ1 genotypes and drug levels to contribute to our understanding of these issues (Australia New Zealand Clinical Trials Register #ACTRN12615000226505, http://www.anzctr.org.au).

This case report shows that chronic DCA therapy can be used without reducing quality of life, as compared to conventional melanoma therapies such as interferon. To determine the optimal protocol for maximum tolerable acute or chronic treatment with DCA, human trials are needed. But more importantly, it still remains to be clarified what dose is required for on-target effects that will be efficacious against cancer. This information is necessary before investing in larger, long term studies on patient outcomes. DCA deserves further investigation in clinical trials as a non-toxic cancer therapy due to its modest cost and low toxicity, and deserves consideration as an off-label cancer therapy.

 

ACKNOWLEDGMENTS

The authors wish to thank Dr. Humaira Khan for her assistance, and also the patient for his support and consent to publish his case.

 

COMMENTS

Case characteristics

The 32-year-old male patient presented with a pigmented lesion on his leg.

 

Clinical diagnosis

The patient was diagnosed with a melanoma.

 

Laboratory diagnosis

Melanoma confirmed by excisional biopsy.

 

Imaging diagnosis

Enlarged inguinal node confirmed to be involved with melanoma (needle biopsy).

 

Pathological diagnosis

Melanoma, BRAF positive.

 

Treatment

Excision of primary lesion with skin graft, sentinel node dissection, multiple excisions of recurrent cutaneous metastases. Traditional therapy stopped and natural anti-cancer therapies started (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). Progression after 3 mo, dichloroacetate (DCA) added. Regression and remission following addition of DCA lasting for over 4 years.

 

Related reports

Computed tomography scan reports demonstrate the course of the disease and response to therapies.

 

Term explanation

DCA: Dichloroacetate sodium; RECIST: Response Evaluation Criteria for Solid Tumours; ECOG: Eastern Cooperative Oncology Group.

 

Experiences and lessons

DCA can act as a pro-apoptotic and cytostatic drug, and can thus achieve regression as well as long-term stabilization of metastatic cancer without serious side effects, as illustrated by this melanoma case.

 

Peer-review

Dr. Khan described a 32-year-old man received DCA therapy, with other medications from natural therapists and maintained in a stabilization state (metastatic melanoma) for over 4 years. It is an interesting case.

 

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FIGURE LEGENDS

Figure 1  Computed tomography scan from March 2012 prior to natural therapies and prior to dichloroacetate therapy. Largest node measured 8 mm in diameter.

Figure 2  Computed tomography scan from July 2012 after 3 mo of natural therapy alone, just prior to the start of dichloroacetate therapy. Largest node measured 22 mm × 20 mm.

Figure 3  Computed tomography scan from November 2012 after 4 mo of dichloroacetate therapy. Largest node measured 10 mm.

Figure 4  Computed tomography scan after 4 years of dichloroacetate therapy without any concurrent conventional cancer therapies. Scan demonstrates absence of cancer re-growth. All nodes measure less than 10 mm.

 

FOOTNOTES

Informed consent statement: The patient described in this manuscript has given consent to publish his case anonymously.

Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invited manuscript

Peer-review started: February 12, 2017

First decision: March 28, 2017

Article in press: May 31, 2017

P- Reviewer: Su CC    S- Editor: Ji FF    L- Editor: A    E- Editor: Lu YJ 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Proof that the cancer industry doesn’t want a cure – even if it’s a pharmaceutical

Tuesday, January 31, 2012 by: PF Louis

http://www.naturalnews.com/034823_cancer_industry_patent_protection_drugs.html

(NaturalNews) A safe and effective cure for cancer has been discovered with a drug that was once used for unusual metabolic problems. Yet, the cancer industry shows no interest with following up on dichloroacetate (DCA) research from University of Alberta in Edmonton, Canada, reported in 2007. That’s because DCA is no longer patented. (1)

That research also confirmed cancer as a metabolic malfunction, not a weird mutation of cells often explained away as a genetic issue. But the medical mafia doesn’t want you to hear about it. But it confirms what most alternative cancer therapists already know.

Since Nixon declared the “war on cancer” in the 1970s, the cancer industry has succeeded with raising money for researching very expensive chemo substances at $50,000 to $100,000 per round or more for toxic therapies that rarely work. (2)

Chemo drugs usually lead to demanding more business with drugs to ease terrible side effects (http://www.naturalnews.com/034761_cancer_drugs_toxicity_Voraxaze.html). Meanwhile, more are getting cancer and more are dying from it, mostly because of the toxic treatments.

Explaining DCA research results

Evangelos Michelakis and the Alberta University research team tested DCA on human cancer cells outside the body and in cancerous mice with profound success. DCA was once used for unusual metabolic disorders. The worst side effects, which rarely occur, include some numbness and an affected gait.

The mice were fed DCA in water, and in weeks they had remarkable tumor shrinkage. This indicates DCA can be taken orally. DCA works by restoring the cells’ mitochondria. Michelakis and his team had discovered that the mitochondria in cancer cells are not permanently damaged and irreparable. This is what mainstream medicine thinks.

With mitochondria malfunctioning, cancer cells use glucose fermentation for survival energy. This fermentation occurs when glycolysis (glucose conversion) occurs in an anaerobic cellular environment, which can be created by benign tumor masses, toxins, and low pH levels.

DCA restores mitochondria in cells to make them function properly. Another function of normal mitochondria is signaling apoptosis, or cellular self destruction. Normal cells die and become replaced constantly. But with cancer cells, the apoptosis signal is nullified, making cancer cells “immortal.” (3)

The Alberta University researchers also realized that glycolysis fermentation in cancer cells produces lactic acid. The lactic acid breaks down the collagen holding those cells together in a tumor. This allows cancer cells to easily break away from a tumor shrinking with mainstream therapies.

The researchers reasoned this is why cancer metastasizes or spreads to different parts of the body or reappears after remission from chemo.

Tragic hypocrisy

Alternative cancer therapies have little or no problem with metastatic cancer or even cancer reoccurring after remission. Most alternative cancers simply cure cancers completely.

DCA offers the cancer industry an opportunity to come up with a pharmaceutical cure that is much cheaper and safer than their current standard of care. Yet the cancer industry is ignoring this opportunity. Instead, DCA is a homeless orphan begging for research funds to avoid legal issues with off label use on cancer. (4)

Alternative cancer practitioners have always simply tried out and when they succeeded shared them with others who cared more about healing than money and power.

The medical mafia has created a matrix that demands big bucks to make big bucks for sick care instead of curing. Everyone in on the scam makes out financially. The cancer industry accuses alternative cancer therapists of quackery and taking advantage of the desperately ill for financial gain. Accusing others of your motives and crimes is called projection.

The medical/pharmaceutical complex is crony capitalism that doesn’t want a cure for cancer from anywhere.

Sources for this article include:

(1) http://www.newscientist.com/article/dn10971

(2) http://www.sawilsons.com/gonzalez2.htm

(3) http://www.cell.com/cancer-cell/retrieve/pii/S1535610806003722

(4) http://www.dca.med.ualberta.ca/Home/Donations/

Chemotherapies that target angiogenesis can increase metastasis threefold- Cancer Cell Journal

Study finds that tumor cells can prevent cancer spread

January 17, 2012 in Cancer Cell Journal

http://medicalxpress.com/news/2012-01-tumor-cells-cancer.html

A new study finds that a group of little-explored cells in the tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis. Published in the January 17 issue of Cancer Cell, these findings suggest that anti-angiogenic therapies – which shrink cancer by cutting off tumors’ blood supply – may inadvertently be making tumors more aggressive and likely to spread.

One approach to treating cancer targets angiogenesis, or blood vessel growth. In this new investigation, senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School (HMS), wanted to find out if targeting a specific cell type, the pericyte, could inhibit tumor growth in the same way that other antiangiogenic drugs do. Pericytes are an important part of tissue vasculature, covering blood vessels and supporting their growth. Kalluri and his colleagues began by creating mice genetically engineered to support drug-induced depletion of pericytes in growing tumors. They then deleted pericytes in implanted mouse breast cancer tumors, decreasing pericyte numbers by 60 percent. Compared with wild-type controls, they saw a 30 percent decrease in tumor volumes over 25 days. However, contrary to conventional clinical wisdom, the investigators found that the number of secondary lung tumors in the engineered mice had increased threefold compared to the control mice, indicating that the tumors had metastasized. “If you just looked at tumor growth, the results were good,” says Kalluri. “But when you looked at the whole picture, inhibiting tumor vessels was not controlling cancer progression. The cancer was, in fact, spreading.” To understand the mechanism behind this increased metastasis, Kalluri and his team examined the tumor’s microenvironment to find out what changes were taking place at the molecular level. They found a fivefold percentage increase in hypoxic areas in tumors lacking pericytes. “This suggested to us that without supportive pericytes, the vasculature inside the tumor was becoming weak and leaky—even more so than it already is inside most tumors—and this was reducing the flow of oxygen to the tumor,” explains Kalluri. “Cancer cells respond to hypoxia by launching genetic survival programs,” he adds. To that end, the investigators found evidence of epithelial-to-mesenchymal transition (EMT), a change that makes the cells more mobile, so they can travel through those leaky vessels to new locations, and makes them behave more like stem cells, so they are better able to survive. Experiments that demonstrated fivefold increases in protein markers of EMT showed that the cells had undergone the change. The team also found a fivefold increase in activation of Met, a receptor molecule that promotes cell migration and growth.

Importantly, the team found that these molecular changes occurred inside the smaller, pericyte-depleted tumors that had increased incidences of secondary tumors in the lungs in the mouse models. “This suggested that smaller tumors are shedding more cancer cells into the blood and causing more metastasis,” says Kalluri. “We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage.” Because cancer therapies such as Imatinib, Sunitinib and others have been shown to decrease pericytes in tumors, the researchers’ next step was to perform the same experiments in mice with primary tumors, only this time, using Imatinib and Sunitinib rather than genetic programs to decrease pericyte numbers. And while both Imatinib and Sunitinib caused a 70 percent pericyte depletion, the end results, stayed the same: metastasis increased threefold. “We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage,” says Kalluri, who corroborated these findings in multiple types of cancer by repeating these same experiments with implanted renal cell carcinoma and melanoma tumors. Additional experiments showed that combining pericyte-depleting drugs with the Met-inhibiting drug helped suppress EMT and metastasis. Finally, to determine if the findings were relevant to patients, the scientists examined 130 breast cancer tumor samples of varying cancer stages and tumor sizes and compared pericyte levels with prognosis. They found that samples with low numbers of pericytes in tumor vasculature and high levels of Met expression correlated with the most deeply invasive cancers, distant metastasis and 5- and 10- year survival rates lower than 20 percent. “These results are quite provocative and will influence clinical programs designed to target tumor angiogenesis,” says Ronald A. DePinho, president of the University of Texas MD Anderson Cancer Center. “These impressive studies will inform and refine potential therapeutic approaches for many cancers.” Meanwhile, for Kalluri, the work suggests that certain assumptions about cancer must be revisited. “We must go back and audit the tumor and find out which cells play a protective role versus which cells promote growth and aggression,” says Kalluri. “Not everything is black and white. There are some cells inside a tumor that are actually good in certain contexts.” Provided by Beth Israel Deaconess Medical Center

Read more at: http://medicalxpress.com/news/2012-01-tumor-cells-cancer.html#jCp