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


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.








(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.




















(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.


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.




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).

DCA and Cancer: Non-Hodgkin’s lymphoma cured in 4 months (Case presentation)

Today we would like to present you our first article based on Dichloroacetate usage benefits as described in case series. This writing will focus on a middle aged man who managed to cure his IV stage Non-Hodgin lymphoma with the use of DCA.

But first – let’s briefly remember some important aspects of this cancer and Sodium dichloroacetate.

Non-Hodgkin lymphoma is a type of cancer that begins in the body‘s immune system cells – T or B lymphocytes. The main histological difference between this malignancy and an other similar illness, the Hodgkin disease, is that the latter cancer has Reed-Sternberg cells present in biopsies. Hodgkin lymphoma is a lot rarer between the two diseases. Besides that, it is also one of the most successfully treated cancers today – 5-year survival rate is about 90 %. (Ref.)

Often one of the first considerably important symptoms of Non-Hodgkin lymphoma is enlarged non-painful lymph nodes. The other signs of the disease include fever, loss of weight, fatigue, cough, shortness of breath and night sweats. This cancer is first suspected when the associated symptoms appear (especially the painless swelling in the lymph nodes) or by accidentally discovering abnormal blood test results. Then the person has to get his blood checked for further analysis.

Above all, computed tomography scans and biopsies play a major role in determining the final diagnosis and the best possible choice of treatment for such patient.

Non-Hodgkin Lymphoma Hodgkin lymphoma
 Symptoms Non-painful lymph node swelling, night sweats, weight loss, fever, fatigue, cough, shortness of breath
 Diagnosis Confirmed via a biopsy of an abnormal lymph node, bone marrow or suspected tumor tissue
 Occurrence More common (6th most widespread cancer in the world) Less common (about ten times fewer cases than Non-Hodgkin lymphoma
 Age groups 45 years and older 15 – 24 years old or 60 years and older
 Treatment Mostly chemotherapy
(R-CHOP chemo regimen)
I or II stage – radiotherapy, ± chemotherapy
III or IV stage – always chemotherapy
(ABVD chemo regimen)
 Prognosis Depends on the type,
recovery is less frequent than in Hodgkin lymphoma
One of the most treatable cancers

Did you know that Non-Hodgkin lymphoma is a quite common cancer ?

Non-Hodgkin lymphoma accounts for 4 % of all new cancer cases. About 20 men and women of 100 000 develop this disease annually.
In 2014 there were about 660 000 people in America who were living with this diagnosis. (Ref.)

The numbers of new Non-Hodgkin lymphoma cases are increasing every year. However, this could be because the diagnostic capabilities of such diseases are getting better. (Ref.)

Non-Hodgkin Lymphoma symphoms and risk factors I DCA and Cancer


A lot of cancers, including Non-Hodgkin lymphoma, are treated with chemotherapy which can help achieve full remission (cured cancer).

Unfortunately, treatment with such medications can result in uncomfortable adverse reactions and long-term health problems. Sometimes the malignancy can relapse (come back) and you have to take chemo drugs all over again.

Not surprisingly, this can be a couple of reasons why people seek alternative cancer therapies by themselves or with the help of other specialists.
One of such alternative treatment choices is Sodium dichloroacetate. Before the idea that this drug could be used to help someone with oncological illnesses, the substance has been used for several decades as a medication for children suffering from congenital mitochondrial diseases.

DCA pharmacokinetics, pharmacodynamics and side effects were studied and discovered long before the accidental findings that this medication could be useful for treating cancer. (Ref.1), (Ref.2)

But how does DCA work ? To put it simply, the most important thing that you should know about the mechanism is that the drug inhibits an important enzyme for cancer – pyruvate dehydrogenase kinase. This leads to various changes in tumor cells.

Firstly, the Warburg effect is diminished. This resumes normal cellular respiration from aerobic glycolysis and lowers elevated intracellular acidity. Secondly, dichloroacetate promotes selective cancer cell apoptosis (cell death) which means that it stops tumor growth and shrinks their volume. Last but not least, DCA can even lower the risk of metastasis. (Ref.)

These sound like great accomplishments considering the fact that the risk of side effects is significantly lower when you take DCA with a couple of other food supplements.

If, however, the adverse reactions do show up – they‘re mostly mild and do not cause much discomfort. These issues are entirely reversible and go away in a couple of days when you stop taking dichloroacetate. (Ref.)

So, this appears to be a promising alternative cancer treatment. And it‘s already helping people who are dealing with oncological diseases. (Ref.1), (Ref.2)

We believe that it could help even more people. That is why we would like to present a case in which a currently 52 year old man cured his cancer.

He had IV stage Non-Hodgkin follicular lymphoma, which was completely resolved as a result of self-medication with DCA (Sodium dichloroacetate).

Non-Hodgkin Lymhpoma I Before and after DCA treatment

The person was at the age of 46 when he started feeling strange. In the last 5 months he lost a lot of weight (50 pounds), had constant fever and drenching night sweats. On top of that, he had enlarged cervical lymph nodes that extended all the way from the top of his neck to the collarbone.

Finally, the man decided to wait no more and got his health checked. The results of a computed tomography scan concluded that there were pathologic lymph nodes in his head, neck, chest, abdomen and pelvis. This was poor news.

Once the male had biopsies taken from his bone marrow and lymph nodes, the diagnosis became clear – he had IV stage Non-Hodgkin follicular lymphoma.

Shortly afterwards the doctors gave him six cycles of R-CHOP chemotherapy (rituximab,cyclophosphamidedoxorubicin,vincristine and prednisolone).

The chemo treatment took several intense months. When he once again had a CT scan performed, the doctors confirmed that he was clear from cancer. He had achieved his first remission (his tumors disappeared).

The man resumed to his former way of life, continued his ordinary daily activities and regularly performed health checks at the physician‘s office. For a year he was completely healthy.

However, after some time the fever, coughing and night sweats came back. Not only that, but he had also lost 11 pounds in two weeks.

Non-Hodgkin Lymphoma I DCA usage protocol for cancerThe male went straight to the doctors and after a couple of diagnostic procedures he received bad news.

He had enlarged lymph nodes on the right side of his head and neck. The cancer was back.

When the man received offers to repeat the treatment, he refused, claiming that chemotherapy and its side effects, especially nausea and vomiting, made him extremely upset and that he would rather avoid the experience.

As a result of his situation, he started searching for alternative cancer treatments that could improve his condition.

Shortly, he learned about DCA, bought this substance online and began treating himself.

His every day ‘‘DCA protocol“ consisted of:
• 1 000 mg Sodium dichloroacetate,
• Vitamin B1 500 mg,
• Alpha-Lipoic acid 1200 mg,
• Green tea leaf extract (Jarrow) 500 mg,
• 10 oz of  Mountain Dew (he would mix it with DCA and drink it afterwards).

The man took this regimen every day. These were the results:

✓ After two weeks his fever, night sweats, fatigue and weight loss started to improve.
✓ After a month of taking DCA his enlarged lymph nodes started to shrink. Two months later no lymph nodes were palpable.
✓ After 71 days of the regimen his symptoms disappeared completely. He recovered his sense of well-being, was full of energy, regained normal appetite and was once again able to have good quality sleep.

Eventually, something astonishing happened. There were no remaining signs of cancer left in his body. This was confirmed by a PET scan at 2008 December (4 months after he had begun his DCA therapy).

All of the previous tumor was gone. The man was cured from Non-Hodgkin lymphoma cancer.

Last time they contacted this person who beat cancer was at the end of 2012. Then he claimed that he still takes 1 000 mg of DCA three times a week together with Thiamine and Alpha-Lipoic acid for prophylaxis.

The 52 year old man feels great. He enjoys his life and works full-time. The last PET scan did not detect any cancerous tissues and cells in the body. Aside from his slightly elevated triglyceride and cholesterol levels, all of his blood tests are normal (the fat and cholesterol are probably higher due to other reasons).

Non-Hodgkin Lymphoma I Before and After DCA treatment PET scan

We prepared this case for presentation based on voluntary medical document distribution to the researchers.

Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models


Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.

Keywords: tumor metabolism, DCA, 17O MRS, hyperpolarized 13C-MRI, 18F-FDG PET


Warburg metabolism (enhanced glycolysis in the presence of oxygen) is a common feature of several malignant tumors and is associated with cancer aggressiveness, invasiveness and poor prognosis []. Because of this high glycolytic rate in various cancers, targeting glucose metabolism is presented as an attractive anticancer approach endowed with a high specificity and limited undesirable side effects []. Indeed, conventional treatments rely on the rapid proliferation process present in cancer cells but also in healthy cells. Treatments targeting glycolytic metabolism should instead specifically alter metabolic adaptations that support the Warburg malignant phenotype, adaptations that are not shared by normal cells. To support drug development and assessment in clinical trials, there is a critical need for dedicated criteria evaluating tumor response to these emerging therapies. Moreover, for new cytostatic agents targeting tumor metabolism, the use of conventional anatomical imaging techniques is not optimal for treatment response assessment [] and only functional and molecular imaging techniques may offer the possibility of an early assessment of the tumor response [].

Recently, we have investigated the effects of dichloroacetate (DCA) in tumor cell lines presenting different metabolic profiles []. DCA is a promising molecule that promotes glucose oxidation over glycolysis by inhibiting the mitochondrial pyruvate dehydrogenase kinase (PDK) and has successfully reached clinical trials []. We found that 5 mM DCA was more effective in glycolytic-phenotype cancer cells, where reduction in cell proliferation was mediated by a reactivation of mitochondrial function and a decrease in glycolytic and pentose phosphate pathway fluxes. Our data suggested that DCA may benefit to patients with highly glycolytic tumors. Therefore, the objective of the present study was to assess the effect of DCA in these prototypical tumor models in vivo, namely the glycolytic MDA-MB-231 human breast cancer model and the oxidative SiHa human cervical cancer model. For this purpose, we used a multi-modality molecular imaging approach using several pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy (17O MRS), glucose uptake, evaluated by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and pyruvate transformation into lactate, measured during hyperpolarized 13C-magnetic resonance imaging (hyperpolarized 13C-MRI), were monitored before and after DCA treatment in tumor bearing mice. Surprisingly, in vivo models did not recapitulate the previously observed in vitro behavior.


To assess the impact of DCA treatment on the metabolism of the models in vivo, oxygen consumption (Figure ​(Figure1),1), glucose uptake (Figure ​(Figure2)2) and lactate flux (Figure ​(Figure3)3) were measured in MDA-MB-231 and SiHa tumors before and 24 hours after DCA treatment.


Figure 1

Effect of dichloroacetate on tumor oxygen consumption in vivo

Tumor H217O signal from representative MDA-MB-231 tumors A. and SiHa tumors B. acquired before, during and after a 2 min inhalation period of the 17O2gas. H217O signal is expressed as relative to the mean baseline signal before 17O2delivery. 17O2 metabolismis not modified by DCA treatment. C. Comparison of the rate of H217O signal after 17O2 delivery in tumors pre and post-treatment. Data are expressed as means ± SEM. Paired tests were two-sided.


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Figure 2

Effect of dichloroacetate on tumor glucose uptake in vivo

Representative 18F-FDG PET images showing MDA-MB-231 A-B. and SiHa C-D.tumor-bearing mouse imaged before and 24 hours after DCA treatment. Tumors are indicated by thin arrows. 18F-FDG uptake is expressed in %ID/g. Images were normalized. DCA does not alter 18F-FDG uptake in MDA-MB-231 and SiHa tumors. E. Comparison of 18F-FDG uptake before and after treatment. Data are expressed as means ± SEM. Paired tests were two-sided.


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Figure 3

Effect of dichloroacetate on tumor lactate production in vivo

Tumor lactate and pyruvate peak intensities after i.v. injection of hyperpolarized 1-13C pyruvate from representative MDA-MB-231 tumors A-B. and SiHa tumors C-D. Lactate production, measured by the Lac/Pyr ratio, in MDA-MB-231 and SiHa tumors before and after treatment E. Data are expressed as means ± SEM. Paired tests were two-sided.

In Figure ​Figure1,1, tumor H217O spectra are presented for representative MDA-MB-231 (Figure ​(Figure1A)1A) and SiHa tumors (Figure ​(Figure1B)1B) during 17O MRS experiments. The results were highly reproducible under the same conditions tested. The evolution of H217O signal, demonstrating the 17O2 metabolism in tumors, was similar before and after DCA treatment in MDA-MB-231 tumors (Figure ​(Figure1A)1A) and in SiHa tumors (Figure ​(Figure1B).1B). In both tumors models, we found that DCA treatment did not majorly impact oxygen consumption, as assessed by the rate of increase in H217O signal (Figure ​(Figure1C).1C). MDA-MB-231 tumors exhibited a slope of 1.02 10-3 ± 0.16 10-3 s-1and 0.91 10-3 ± 0.09 10-3 s-1 before and after treatment respectively (n=5, P=0.5366). For SiHa tumors, the slopes were 0.85 10-3 ± 0.14 10-3 s-1 under baseline condition and 0.79 10-3 ± 0.11 10-3 s-1 post-treatment (n =5, P=0.2892).

18F-FDG uptake (%ID/g) measured in both tumor models under baseline and post-treatment conditions are presented in Figure ​Figure2.2. In both tumor models, we found that DCA treatment did not lead to a significant change in the uptake of 18F-FDG (Figure 2A-2D), assessing a limited impact of DCA on glucose uptake (Figure ​(Figure2E).2E). %ID/g measured on PET images (mean ± SEM) were 1.88 ± 0.12 under baseline condition and 1.78 ± 0.11 after treatment for MDA-MB-231 tumors (n=7, P=0.2120) and 1.79 ± 0.21 under baseline condition and 1.89 ± 0.19 after treatment for SiHa tumors (n=7, P=0.0813).

The influence of DCA treatment on pyruvate transformation into lactate was measured after hyperpolarized 1-13C pyruvate injection during hyperpolarized 13C-MRS studies (Figure ​(Figure3).3). Representative pyruvate and lactate peak intensities over time of MDA-MB-231 tumors and SiHa tumors captured before and 24 hours after DCA treatment are shown in Figure 3A-3D. Lactate production was reduced after DCA treatment only in SiHa tumors (Figure ​(Figure3E).3E). Lactate/pyruvate ratio (Lac/Pyr) shifted from 0.55 ± 0.05 to 0.48 ± 0.04 in MDA-MB-231 tumors (n=7, P=0.3105) and from 0.82 ± 0.05 to 0.63 ± 0.07 in SiHa tumors (n=7, P=0.0348).

We also evaluated the magnitude of response to the treatment by measuring the variation within the above biomarkers between baseline and post-treatment conditions (Figure ​(Figure4).4). No differences in oxygen consumption and lactate flux measurements were observed between MDA-MB-231 and SiHa tumors during the treatment (P>0.05) (Figure 4A, 4C). Only a small but significant difference in behavior was observed for 18F-FDG uptake measurements (P=0.0240) (Figure ​(Figure4B).4B). MDA-MB-231 tumors decreased their 18F-FDG uptake after treatment (n=7, -5.4 ± 3.5 %) compared to SiHa tumors (n=7, +6.7 ± 3.1 %).


Figure 4

DCA does not significantly influence the metabolism of glycolytic tumors compared to oxidative tumors, as assessed by 17O2 metabolism A., 18F-FDG uptake B. and pyruvate transformation into lactate C. measurements in vivo

The magnitude of response to dichloroacetate (variation) is identical in both models, only a small difference in behavior is observed for 18F-FDG uptake. Data are expressed as means ± SEM. Unpaired tests were two-sided.


In this study, the impact of DCA on tumors presenting different metabolic profiles was evaluated using molecular imaging in vivo. Recent findings identified that DCA preferentially impairs glycolytic cells compared to oxidative cells. The purpose of the present study was to establish the relevance of these findings in vivo using the same prototypical tumor models as in our in vitro study [], namely the MDA-MB-231 human breast cancer model reported as glycolytic [] and the SiHa human cervical cancer model documented as oxidative []. The dose and administration scheme were selected based on previous reports attesting the efficacy of DCA in tumors [].

In vitro, we previously identified clear effects of DCA treatment on oxygen consumption, glucose consumption and lactate uptake in glycolytic MDA-MB-231 human breast cancer cells. On the other hand, the metabolic activity of oxidative SiHa human cervical cancer cells was not altered by DCA treatment. Using a multi-modality imaging project, we were not able to recapitulate these findings in vivo. Pre-treatment, MDA-MB-231 and SiHa tumors exhibit the same metabolic profile. As MDA-MB-231 and SiHa tumors were previously described as hypoxic under baseline condition [], we highlighted here that both tumor models exhibit a glycolytic phenotype under anaerobic condition. Post-treatment, glycolytic MDA-MB-231 tumors do not appear more impacted than oxidative SiHa tumors (Figure 1-4). Also, some marginal metabolic changes were identified such as a significant decreased lactate production in SiHa tumors (Figure ​(Figure3E)3E) or a decreased 18F-FDG uptake in MDA-MB-231 tumors (Figure ​(Figure4B).4B). Together, those findings did not highlight a clear metabolic shift in MDA-MB-231 tumors or in SiHa tumors treated with DCA during 24 hours (Supplementary Figure S1). This inability to observe any treatment response in vivo could not be attributed to any differences in growth rate between the tumor models under study (Supplementary Figure S2). Also, the measurement repeatability was formerly established using the same tumor models []. Our study demonstrated that the tumor metabolic response to DCA was dramatically different between in vitro and in vivo conditions.

Because of its good tolerability and safety, DCA has been universally exploited to lower lactate levels in acquired or congenital forms of lactic acidosis []. In 2007, Bonnet and colleagues investigated the effects of DCA in cancer and discovered that DCA was promoting apoptosis in vitro and decreasing tumor growth in vivo []. Since then, this orally available and cheap molecule has been further investigated in vitro, in vivo and successfully reached clinical trials. The first data available from the clinical trials indicate that DCA appears to be efficient in adults in solid and brain tumors []. However, no firm conclusions stand out in advanced non-small cell lung cancer []. In another recent study of Feuerecker and co-workers, promotion of tumor growth was even observed after DCA treatment in neuroblastoma tumors []. These studies indicate that response to DCA treatment may drastically vary among tumor types.

The redirection of glucose metabolism from glycolysis to oxidation leading to the inhibition of proliferation and the induction of caspase-mediated apoptosis was initially proposed as the generic mechanism of action of DCA. In a recent phase I study in patients with advanced solid tumors, decreased 18F-FDG uptake was observed after DCA therapy, supporting the use of 18F-FDG uptake as a potential biomarker of response to DCA []. Also, hyperpolarized 13C-pyruvate MRI has already been used in several preclinical studies to monitor DCA effect in solid tumors [], but also in cardiac [] and brain studies []. In the present study, 18F-FDG uptake was unchanged after DCA treatment (Figure ​(Figure2E).2E). This suggests that DCA treatment does not impair glucose uptake and phosphorylation but could potentially impact downstream transformation of glucose. However, no effects on bicarbonate production were detected that could demonstrate changes in energy metabolism from glycolysis to oxidative phosphorylation (Supplementary Figure S3). Recent findings suggested that DCA may also act by other mechanisms. While a possible disruption of the balance between fatty acid β-oxidation and glucose oxidation has already been suggested as an additional mechanism involved in the overall effects of DCA in vivo (as reviewed by []), PDK inhibitors may potentially induce other compensatory mechanisms that could limit the impact of such drugs on global tumor metabolism. The anti-cancer effects of DCA appear to rely on multiple mechanisms depending on the drug concentration, drug administration scheme [] and cell type []. Also, a change in PDK isoform expression between in vitro and in vivo model could also greatly influence the effect of DCA on tumor metabolism in vivo. Indeed, oncogene regulation and tumor microenvironment, like extracellular acidosis, can affect PDK isoform expression [], possibly leading to the expression of a PDK isoform less sensitive to DCA effects. Our findings are consistent with a recent study highlighting that tumor microenvironment could be as important as the (epi) genetic profile to shape the tumor phenotype []. Further investigations using relevant isogenic cell clones with ability to form tumors in vivo should be considered to determine the effects of DCA on energy metabolism in vivo.

In conclusion, our multi-modality imaging study identified major discordances between in vitro and in vivo metabolic responses to DCA treatment, in cancer models presenting distinct metabolic profiles. Results suggest preferring implanted tumors and spontaneous cancer models to study DCA treatment within the milieu of the tumor microenvironment. Overall, further investigations are required to elucidate the impact of different tumor microenvironments on metabolic effects of DCA and its impact for clinical use.


Cell culture

MDA-MB-231 (human breast cancer) and SiHa (human cervix squamous cell carcinoma) cell lines (American Type Culture Collection [ATCC]), were routinely cultured in Dulbecco’s modified Eagle’s medium containing 4.5g/l glucose supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin.

Animal housing

Animal studies were undertaken in accordance with Belgian and the Université catholique de Louvain ethical committee regulations (agreements number UCL/2010/MD/001 and UCL/2014/MD/026). Hyperpolarized 13C-MRI experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animal Resources (National Research Council, 1996) and approved by the National Cancer Institute (NCI) Animal Care and Use Committee.

Tumor implantation and animal experiments

A total of 107 MDA-MB-231 cells or 107 SiHa cells, amplified in vitro, were collected by trypsinization, washed three times with Hanks balanced salt solution and resuspended in 200 μL of a 1:1 mixture of Matrigel (BD Biosciences) and Hanks balanced salt solution. For 17O MRS and PET scan experiments, the tumor cells were inoculated subcutaneously into the hind thigh of nude NMRI female mice (Janvier Le Genest-Saint-Isle, France). For hyperpolarized 13C-MRI experiments, the tumor cells were inoculated subcutaneously into the hind thigh of athymic nude female mice (Frederick Cancer Research Center, Animal Production, Frederick, MD, USA). The experiments were performed when tumors reached 7 mm (at this tumor size, necrosis was less than 5% as characterized by Hematoxylin Eosin staining).

To assess the effects of DCA on tumor metabolism using biomarkers, all animals have undergone imaging before and after treatment, with one day between each measurement. Dichloroacetate sodium (Sigma-Aldrich) was administered intraperitoneally (200 mg/kg) after baseline measurements to the mouse. Another dose was given 24 hours after the first dose injection. Post-treatment measurements were initiated 1 hour after treatment administration. This administration scheme is consistent with previous studies attesting the effects of DCA in tumors using hyperpolarized 13C-MRI []. The imaging protocol is summarized in Figure ​Figure55.


Figure 5

Experimental protocol

Mice were anesthetized by isoflurane inhalation (Forene, Abbot, England) mixed with air in a continuous flow (2 L/min). Animals were warmed (approximately 35°C) throughout the anesthesia period.

17O MRS experiments

For oxygen consumption experiments, 17O MRS was performed on an 11.7 T (Bruker, Biospec) controlled by Paravision 6.0 (Bruker, Ettlingen, Germany). Experiments were carried out using a 1H/17O Bruker surface coil system positioned over the tumor mass. Anatomical images were firstly acquired using a T2-weighted axial turbo RARE sequence (TR = 2500ms; TE = 30ms; rare factor = 8; NA = 2; FOV = 25x25mm2; resolution: 98 x 98 μm2; 1 mm slice thickness). 17O MRS measurements were carried out using a nonlocalized, single-pulse sequence (TR = 16.5 ms; NA = 600; repetition: 120; Tacq = 20 min; Acq BW = 5000 Hz; FA = 20°). For 17O MRS sequence, the 90° reference pulse was optimized previously on natural abundance H217O samples.

To measure tumor oxygen consumption during the 17O2 delivery, a total of 120 17O-spectra were collected in about 20 min, before, during and after a 2 min inhalation period of the 17O2 mixture. The integrals of the H217O peaks over time were measured using a home-made program written in Matlab (The MathWorks Inc., Natick, MA, USA). H217O signal was then expressed as relative to the mean baseline signal before 17O2 delivery. The mean signal of the final steady state (sfinal) during the post-inhalation period was calculated between 1100 and 1200 s. We considered that the steady state was reached when the signal stood between sfinal ± 5 % of signal variation. The slope during the linear incorporation phase was measured between 600 sec and the time point when steady state was reached.

PET/CT imaging

Whole-body PET imaging was performed on a dedicated small-animal PET scanner (Mosaic, Philips Medical Systems, Cleveland, USA) with a spatial resolution of 2.5 mm (FWHM). The PET scans were followed by whole-body acquisitions using a helical CT scanner (NanoSPECT/CT Small Animal Imager, Bioscan Inc., DC, USA). For each breathing condition, anesthetized mice were injected 120 μl intraperitoneally with 11.1-14.8 MBq of 18F-FDG (Betaplus Pharma, Brussels, Belgium). A 10 min transmission scan was first obtained in a single mode using a 370 MBq 137Cs source for attenuation correction. A 10 min static PET acquisition was then performed after a 60 min resting period. After the correction with attenuation factors obtained from the transmission scan, images were reconstructed using a fully 3D iterative algorithm (3D-RAMLA) in a 128 x 128 x 120 matrix, with a voxel size of 1 mm3. After PET acquisition, anesthetized animals were transferred on the same bed from the PET scanner to the CT scanner (x-ray tube voltage: 55 kVp; number of projections: 180; exposure time 1000 ms) for anatomical reference. The CT projections were reconstructed with a voxel size of 0.221 x 0.221 x 0.221 mm3. Regions of Interest (ROIs) were delineated on PET images using PMOD software (PMOD™, version 3.403, PMOD technologies Ltd, Zurich, Switzerland). 2D ROIs were established on consecutive transversal slices using a 50% isocontour tool (ROI including the pixel values larger than 50% of the maximum pixel) that semi-automatically defined a 3D Volume of Interest (VOI) around the tissue of interest. To avoid overestimation of the uptake within the VOI, PET/CT fused images where used to discriminate hot pixels coming from the neighboring tissues like urinary bladder. Using the mean uptake within this VOI, the global tracer uptake was assessed in tumors and expressed as percentage of injected dose per gram of tissue (%ID/g).

Hyperpolarized 13C-MRI studies

1-13C pyruvic acid (30 μL), containing 15 mM OXO63 and 2.5 mM gadolinium chelate ProHance (Bracco Diagnostics, Milano, Italy), was hyperpolarized at 3.35T and 1.4K using the Hypersense DNP polarizer (Oxford Instruments, Abingdon, UK) according to the manufacturer’s instructions. After 60-90 min, the hyperpolarized sample was rapidly dissolved in 4.5 mL of a superheated alkaline buffer that consisted of 50 mM Tris(hydroxymethyl)aminomethane, 75 mM NaOH, and 100 mg/L ethylenediaminetetraacetic acid. The hyperpolarized 1-13C pyruvate solution (96 mM) was intravenously injected through a catheter placed in the tail vein of the mouse (12 μL/g body weight). Hyperpolarized 13C MRI studies were performed on a 3T scanner (MR Solutions, Guildford, UK) using a home-built 13C solenoid leg coil. After the rapid injection of hyperpolarized 1-13C pyruvate, spectra were acquired every second for 240 seconds using a single pulse sequence. Data were analyzed in a model free approach using the lactate/pyruvate ratio, calculated from the areas under the curves of the 1-13C lactate peak and the 1-13C pyruvate peak [].

Statistical analysis

Analysis was performed using the GraphPad Prism 7 software. Results are expressed as means value of parameter ± SEM. All statistical tests were two-sided. Paired t-test was used to compare mean changes between groups (baseline vs. post-treatment) for each tumor model, and unpaired t-test was used to compare mean changes between the two tumor models. Results with P < 0.05 (*), <0.01 (**), or <0.001 (***) were considered to be statistically significant.