Redefining
Cancer
Treatment
Redefining
Cancer
Treatment
DCA is typically priced between £20 to £100 per month depending on the supplier and formulation.
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Dichloroacetate (DCA) is a small molecule with growing interest in cancer research due to its ability to target the altered metabolism of cancer cells. Here’s an overview of its anti-cancer properties and mechanisms:
DCA primarily works by inhibiting pyruvate dehydrogenase kinase (PDK), an enzyme that regulates the activity of pyruvate dehydrogenase (PDH). This inhibition shifts cancer cell metabolism from glycolysis (the Warburg effect) to oxidative phosphorylation in the mitochondria. This metabolic switch has several downstream effects:
Reversal of the Warburg Effect: Cancer cells typically rely on glycolysis for energy production, even in oxygen-rich environments. DCA restores mitochondrial function, increasing glucose oxidation and reducing lactate production147.
Induction of Apoptosis: By restoring mitochondrial activity, DCA increases reactive oxygen species (ROS) production and promotes cytochrome c release, triggering caspase-mediated apoptosis1611.
Reduction in Tumour Growth: Preclinical studies have shown that DCA reduces tumour size in various cancer models, including lung, colorectal, and endometrial cancers41011.
Tumour Suppression: DCA has demonstrated significant anti-tumour effects in in vitro and in vivo studies across multiple cancer types, including lung, breast, glioblastoma, colorectal, and ovarian cancers61011.
Metabolic Modulation: It reduces mitochondrial membrane potential in cancer cells while sparing normal cells, highlighting its selective action10.
Synergistic Effects: DCA enhances the efficacy of chemotherapy and radiotherapy by sensitising cancer cells to these treatments. For example, it has shown synergy with pemetrexed in lung adenocarcinoma models5.
Case reports and small-scale studies have shown tumour shrinkage and improved survival in some patients with advanced cancers treated with DCA. Cancers studied include brain, lung, colorectal, and pancreatic cancers29.
However, larger clinical trials are needed to confirm these findings. Mixed results have been reported regarding overall survival benefits24.
Selectivity: DCA targets cancer-specific metabolic pathways without significantly affecting normal cells.
Oral Availability: It is a small molecule that can be administered orally, making it accessible compared to many other cancer therapies6.
Cost-Effectiveness: As a generic drug, DCA is relatively inexpensive compared to newer targeted therapies6.
Side Effects: Neurotoxicity is a noted side effect of DCA, which limits its long-term use3.
Resistance Mechanisms: Some highly invasive tumour’s show resistance to DCA-induced apoptosis. Further research is needed to understand these mechanisms8.
Combination Therapies: While promising as a standalone treatment, DCA’s efficacy may be enhanced when combined with other therapies like chemotherapy or immunotherapy511.
Tumour Lysis Syndrome Risk: Rapid tumour cell death induced by DCA could lead to complications like tumour lysis syndrome when used alongside other treatments2.
Research is ongoing to optimise dosing regimens, explore combination therapies, and develop derivatives like diisopropylammonium dichloroacetate (DADA) with improved efficacy and reduced toxicity5. Additionally, efforts are being made to identify biomarkers for predicting patient response to DCA therapy4.
In summary, Dichloroacetate holds significant promise as a metabolic-targeting therapy for cancer due to its ability to reverse the Warburg effect and selectively induce apoptosis in cancer cells. While preclinical data are robust, further clinical trials are essential to establish its role in standard cancer care.
A standard dosage for Dichloroacetate (DCA) in cancer treatment has not been universally established due to its experimental status and variability in patient responses.
However, typical dosing regimens have been explored in clinical and case studies:
Oral Administration: Common doses range from 6.25 mg/kg to 12.5 mg/kg taken twice daily (BID), often cycling two weeks on and one week off to minimise side effects like peripheral neuropathy123.
Intravenous Administration: Doses vary widely, with reports of weekly infusions starting at 3,000 mg and escalating to 4,500–5,000 mg per session depending on patient tolerance13.
Maximum Tolerated Dose: Attempts to increase oral doses to 500 mg three times daily (TID) have led to adverse events such as liver enzyme elevation and neuropathy, highlighting the need for careful dose adjustments26.
Maintenance doses are often reduced to mitigate side effects, with 6.25 mg/kg BID being a safer long-term option34. While these dosing guidelines provide a framework, individual factors like body weight, cancer type, and concurrent therapies influence the optimal dosage. Further clinical trials are needed to define a universally accepted standard.
Brain Tumours, Breast Cancer, Lung Cancer
Dichloroacetate (DCA) has been associated with a range of side effects, which are generally dose-dependent and vary in severity.
Here is an overview of the most commonly reported adverse effects:
Peripheral Neuropathy: The most frequently reported side effect, characterised by tingling, numbness, or burning sensations, primarily in the toes and fingers. It is usually reversible upon discontinuation of DCA346.
Central Nervous System Effects: These include sedation, confusion, memory loss, hallucinations, agitation, depression, tremors, and gait abnormalities14.
Muscular Rigidity and Tremors: Some patients have reported muscular rigidity in the upper extremities and hand tremors2.
Nausea, vomiting, heartburn, diarrhoea, and indigestion are relatively common. These can often be managed with antacid medications such as proton pump inhibitors (e.g., pantoprazole)14.
Mild elevations in liver enzymes (AST, ALT, GGT) have been observed in some patients. These changes are typically asymptomatic and reversible upon stopping DCA16.
Some patients experience pain at the site of their tumours shortly after starting DCA therapy. This may indicate increased apoptosis and tumour cell death16.
Fatigue
Low calcium levels
Thrombocytopenia (low platelet count), though rare4.
Tumour Lysis Syndrome: A rare complication that may occur due to rapid tumour cell death in patients with large or highly active tumours (e.g., leukaemia or lymphoma)6.
Carcinogenicity Concerns: Animal studies have suggested a potential link between high doses of DCA and liver cancer. However, no human studies have confirmed such effects at therapeutic doses used in cancer treatment17.
Most side effects are reversible upon discontinuation or dose reduction.
Peripheral neuropathy risk can be mitigated by cycling DCA treatment (e.g., two weeks on, one week off) or using lower maintenance doses.
Close monitoring by healthcare professionals is essential to manage side effects effectively.
While DCA is generally well-tolerated at therapeutic doses, its side effects underscore the importance of medical supervision during treatment.
Dichloroacetate (DCA) has been investigated in combination with multiple therapies to enhance anticancer efficacy, reduce drug resistance, and minimise side effects.
Below are key combinations studied in mostly preclinical and some clinical settings:
Cisplatin
Paclitaxel
Enhanced cell death in NSCLC by inhibiting autophagy and overcoming paclitaxel resistance4.
Doxorubicin
Combined with DCA in liver cancer (HepG2), disrupting antioxidant defences to amplify oxidative damage4.
Temozolomide
A Phase II clinical trial (NCT05120284) is testing DCA with temozolomide and radiotherapy in newly diagnosed glioblastoma patients7.
Gefitinib/Erlotinib:
DCA showed additive/synergistic effects with EGFR inhibitors in NSCLC, particularly in colony growth inhibition over extended treatment periods1.
Colorectal Cancer:
Lower DCA doses (5–10 mM) combined with radiation (4–8 Gy) increased DNA damage and reduced CRC cell survival2.
Breast Cancer:
DCA radiosensitised hypoxic EMT6 and 4T1 cells in vitro, though in vivo tumour growth delays were not observed5.
Curcumin:
Synergistic apoptosis induction in liver cancer (Huh-7 cells), allowing reduced DCA doses while maintaining efficacy6.
Salinomycin:
A potent synergy in colorectal cancer (HCT116/DLD-1) via inhibition of multidrug resistance proteins8.
Recombinant Arginase:
Combined with DCA in triple-negative breast cancer, triggering cell cycle arrest and p53 activation4.
Combination therapies often leverage DCA’s metabolic reprogramming to:
Reverse chemoresistance by modulating PDK2 expression4.
Amplify oxidative stress to enhance radiotherapy or chemotherapy-induced DNA damage26.
Reduce mitochondrial reserve capacity in hypoxic tumors5.
While preclinical data are promising, clinical validation remains limited. Ongoing trials (e.g., glioblastoma7) aim to translate these findings into therapeutic protocols.
US National Library of Medicine research on DCA
Europe PMC research on DCA
Pubmed research on DCA
The quality of life (QoL) impact of Dichloroacetate (DCA) treatment in cancer patients is influenced by its potential benefits and side effects. Here’s an overview based on preclinical and clinical findings:
Reduction in Cancer-Related Fatigue (CRF):
DCA has shown promise in alleviating cancer-related fatigue, a common and debilitating condition that significantly affects QoL. In preclinical studies, DCA preserved physical function, motivation, and muscle performance in tumour-bearing mice without interfering with standard cancer treatments like chemotherapy or immunotherapy145.
By reducing oxidative stress and circulating lactate levels, DCA may help maintain energy levels and physical activity in patients, potentially improving their overall well-being14.
Stable Disease with Minimal Impact on Daily Life:
Case reports suggest that DCA can stabilise advanced cancers for extended periods without significantly reducing QoL. For example, a patient with stage IV colon cancer experienced stable disease for nearly four years on DCA therapy without concurrent chemotherapy, maintaining a good quality of life28.
Cytostatic Effects:
Unlike aggressive cytotoxic therapies, DCA often acts as a cytostatic agent, slowing tumour growth rather than causing rapid cell death. This may result in fewer severe side effects compared to conventional treatments8.
Peripheral Neuropathy:
Fatigue and Mental Fog:
Gastrointestinal Side Effects:
Nausea, heartburn, and digestive issues are occasionally reported but are generally mild and manageable with supportive care8.
Liver Enzyme Elevations:
Tumour-Related Pain:
Temporary pain at the tumour site has been reported during the initial stages of treatment, likely due to tumour cell apoptosis. This typically resolves over time8.
For many patients, DCA appears to offer a favourable balance between therapeutic benefits and manageable side effects. Its ability to preserve physical function and reduce fatigue could enhance quality of life during cancer treatment.
However, side effects such as neuropathy or mental fog may temporarily impair QoL for some patients. These risks underscore the importance of careful dosing, monitoring, and supportive care during treatment.
Ultimately, the impact on QoL will vary depending on individual factors like cancer type, disease stage, comorbidities, and tolerance to the drug. Further clinical trials are needed to better quantify QoL outcomes in larger patient populations.
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DCA can generally be procured through online vendors or research chemical suppliers, though its use remains largely within an experimental context.
Patient demographics and characteristics that may influence the suitability of Dichloroacetate (DCA) therapy are still being studied, but some insights have emerged from preclinical and clinical research. These factors include genetic, metabolic, and tumour-specific considerations that could help identify patients most likely to benefit from DCA.
Mitochondrial Hyperpolarisation: DCA is most effective in cancers with hyperpolarised mitochondria, which are common in many solid tumour’s such as glioblastoma, breast, prostate, endometrial, and lung cancers. These tumour’s rely on glycolysis (the Warburg effect) for energy production, making them more susceptible to DCA’s metabolic reprogramming effects18.
Cancer Types with Limited Treatment Options: DCA has shown promise in cancers like recurrent glioblastoma and advanced lung cancer, where conventional therapies have limited efficacy8. However, it may be less effective in cancers lacking mitochondrial hyperpolarisation, such as small-cell lung cancer, lymphomas, neuroblastomas, and sarcomas8.
GSTZ1 Polymorphisms: The enzyme glutathione transferase zeta 1 (GSTZ1) is responsible for metabolising DCA. Genetic variations (haplotypes) in the GSTZ1 gene affect DCA clearance and toxicity. Patients with certain haplotypes may require personalised dosing to minimise side effects like neuropathy14.
Studies on prostate cancer cell lines derived from African American and Caucasian patients revealed differences in DCA’s effectiveness when combined with chemotherapy. While DCA inhibited cell proliferation in both groups, it sensitised African American cells to doxorubicin and increased taxol-induced cell death only in Caucasian cells. This suggests that ethnicity-linked tumours aggressiveness and drug responsiveness may influence outcomes2.
Patients with elevated lactate levels or tumours showing high glucose uptake on PET imaging may be better candidates for DCA therapy. These features indicate reliance on glycolysis, which DCA targets by shifting metabolism toward oxidative phosphorylation38.
Younger patients may metabolise DCA differently due to age-related differences in GSTZ1 activity. Older patients might experience slower clearance of the drug, potentially increasing the risk of side effects like neuropathy4.
Patients with severe lactic acidosis or mitochondrial disorders have been treated with DCA in non-cancer contexts, suggesting that individuals with metabolic abnormalities might tolerate the drug well under careful monitoring34. However, those with pre-existing neuropathy or liver dysfunction may require closer observation due to the risk of exacerbating these conditions.
While no definitive patient demographic has been established for optimal use of DCA in cancer therapy, factors such as tumour type (e.g., solid tumours with mitochondrial hyperpolarisation), genetic polymorphisms (GSTZ1 haplotypes), metabolic profile (glycolysis-dependent tumours), and ethnicity-related tumour behaviour can guide patient selection. Personalised dosing based on these characteristics is likely necessary to maximise efficacy while minimising side effects.
Further clinical trials are needed to refine these criteria and establish clear guidelines for patient selection.
Resistance mechanisms to Dichloroacetate (DCA) in cancer therapy have been identified, primarily involving genetic, metabolic, and compensatory adaptations in tumours. Below are the key factors that reduce DCA’s efficacy:
PDK2 Overexpression:
PDK2 overexpression in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) has been linked to chemoresistance. DCA’s inhibition of PDK can be counteracted by compensatory upregulation of PDK isoforms, particularly PDK2, sustaining glycolysis and mitochondrial hyperpolarisation18.
miR-543 Overexpression:
In oxaliplatin-resistant CRC, elevated miR-543 levels suppress PTEN, activating the Akt/mTOR survival pathway. DCA reverses this by downregulating miR-543, but tumours with persistent miR-543 overexpression may resist DCA’s pro-apoptotic effects2.
miR-149-3p/p53 Axis:
Wild-type p53 regulates miR-149-3p, which targets PDK2. Mutant p53 in CRC disrupts this axis, reducing DCA’s ability to restore chemosensitivity to 5-FU1.
Persistent Mitochondrial Hyperpolarisation:
Some tumours maintain hyperpolarised mitochondrial membranes despite DCA treatment, eviting apoptosis. This is observed in small-cell lung cancer and sarcomas, which inherently lack mitochondrial hyperpolarisation34.
Reduced ROS Production:
Tumours with enhanced antioxidant defences (e.g., glutathione upregulation) neutralise DCA-induced reactive oxygen species (ROS), blunting apoptotic signals68.
Lactate Shuttling:
Glycolysis-derived lactate in the tumour microenvironment supports neighbouring cancer cell survival, counteracting DCA’s metabolic shift. This is prominent in hypoxic tumors8.
Hypoxia-Inducible Pathways:
Hypoxia stabilises HIF-1α, which promotes glycolysis and PDK expression, overriding DCA’s PDK inhibition34.
MIF Gene Overexpression:
Macrophage migration inhibitory factor (MIF) promotes glycolysis and suppresses oxidative phosphorylation. Tumors with high MIF expression resist DCA’s metabolic reprogramming and apoptosis induction67.
PTEN Loss:
PTEN deficiency activates the PI3K/Akt/mTOR pathway, enhancing cell survival and reducing DCA’s efficacy in CRC2.
GSTZ1 Polymorphisms:
Genetic variants in glutathione transferase zeta 1 (GSTZ1) alter DCA metabolism, leading to variable drug exposure. For example, GSTZ1A carriers metabolize DCA faster, reducing its therapeutic window68.
Akt/mTOR Activation:
In CRC, Akt/mTOR signalling downstream of PTEN loss promotes cell survival, diminishing DCA’s pro-apoptotic effects2.
Autophagy Induction:
Some tumours activate autophagy to survive metabolic stress induced by DCA, particularly in hypoxic conditions8.
Cell Line-Specific Responses:
Colorectal cancer cells (e.g., HT29 vs. LoVo) show divergent responses to DCA, with some arresting in G2 phase rather than undergoing apoptosis. This suggests intrinsic resistance mechanisms tied to genetic or epigenetic variability5.
Combination therapies targeting these resistance pathways—such as DCA with mTOR inhibitors (e.g., everolimus), Akt inhibitors, or miR-543 antagonists—may improve outcomes. Monitoring biomarkers like PDK2, MIF, and miR-543 levels could help identify resistant tumours and guide treatment adjustments.
Preclinical studies on Dichloroacetate (DCA) have extensively explored its anticancer potential, focusing on its ability to target cancer metabolism.
Here’s an outline of key findings:
DCA inhibits pyruvate dehydrogenase kinase (PDK), reactivating the pyruvate dehydrogenase complex (PDH). This shifts cancer cells from glycolysis (the Warburg effect) to mitochondrial oxidative phosphorylation, reversing metabolic reprogramming and restoring apoptosis via:
Mitochondrial depolarisation, reducing hyperpolarisation in cancer cells16.
Increased reactive oxygen species (ROS), triggering cytochrome c release and caspase activation14.
Preclinical models demonstrate tumour suppression in:
Glioblastoma: Reduced proliferation and induced apoptosis in vitro and in vivo14.
Breast, lung, prostate, and endometrial cancers: Mitochondrial depolarisation and apoptosis via ROS146.
Colon cancer: Mixed results, with some studies showing delayed cell death and others showing resistance46.
Pancreatic and ovarian cancers: Reduced tumour volume and metastasis in animal models46.
DCA enhances conventional treatments:
Chemotherapy: Synergy with cisplatin, doxorubicin, and taxanes by overcoming chemoresistance146.
Radiotherapy: Radiosensitisation in colorectal and breast cancer models via increased oxidative stress4.
Natural compounds: Curcumin and salinomycin amplify apoptosis in liver and colorectal cancers46.
Variable sensitivity: Tumours without mitochondrial hyperpolarisation (e.g., lymphomas, sarcomas) show resistance14.
Toxicity: High doses (e.g., 200 mg/kg/day) induce cell death in noncancerous cells, raising safety concerns46.
Inconsistent results: Some colon cancer models showed no significant apoptosis46.
Effective doses: 50–200 mg/kg/day in preclinical models, reducing tumour volume and metastasis6.
Neurotoxicity and variable drug clearance (linked to GSTZ1 polymorphisms) complicate dosing35.
Targeted delivery systems to improve bioavailability and reduce side effects56.
Biomarker-driven approaches (e.g., PET imaging for glucose uptake) to identify responsive tumors13.
Cancer stem cell targeting: DCA reduces stem cell fractions in some models, potentially preventing recurrence56.
In summary, preclinical data highlight DCA’s potential as a metabolic therapy, but variability in efficacy and toxicity underscores the need for optimised formulations and biomarker-guided clinical trials.
Information on active clinical trials is limited and requires further investigation. For current trials, see: ClinicalTrials.gov DCA research.
Genetic markers influencing Dichloroacetate (DCA) efficacy and toxicity have been identified, primarily linked to polymorphisms in the GSTZ1 gene and tumour-specific metabolic characteristics.
Here’s a breakdown of key findings:
Metabolic Clearance:
The enzyme glutathione transferase zeta 1 (GSTZ1) is responsible for DCA metabolism. Genetic variations in GSTZ1 (haplotypes A–E) affect drug clearance and toxicity:
High-activity variants (GSTZ1A*) correlate with faster DCA metabolism, leading to lower plasma concentrations and reduced efficacy.
Low-activity promoter genotypes (e.g., rs7160195 -1002A) result in slower metabolism, increasing DCA exposure and therapeutic response but raising neuropathy risk36.
Patients with the EGM/EGM genotype show markedly higher DCA plasma levels and severe neuropathy6.
Mitochondrial Hyperpolarisation:
Tumours with hyperpolarised mitochondria (e.g., glioblastoma, breast, prostate, lung cancers) respond better to DCA, while those lacking this feature (e.g., small-cell lung cancer, lymphomas) show resistance14.
MIF Gene Interaction:
In lung cancer, DCA reduces tumour growth by elevating citric acid levels and suppressing macrophage migration inhibitory factor (MIF) gene expression. Lower MIF levels correlate with metabolic reprogramming and apoptosis induction24.
Prostate cancer cells from African American patients showed increased sensitivity to DCA combined with doxorubicin, whereas Caucasian-derived cells responded better to DCA with taxanes. This suggests ethnicity-associated genetic factors may influence treatment outcomes4.
Personalised Dosing:
GSTZ1 genotyping could guide dosing to balance efficacy (e.g., higher doses for GSTZ1A carriers) and toxicity (lower doses for rs7160195 -1002A carriers)36.
Biomarker Potential:
Elevated tumour lactate levels or PET-positive glucose uptake may predict DCA responsiveness in glycolysis-dependent cancers1.
GSTZ1 polymorphisms are the best-characterised genetic markers affecting DCA pharmacokinetics and toxicity. Tumour mitochondrial status and MIF expression further refine efficacy predictions. While these findings support personalised therapy, clinical validation in larger trials is needed to translate biomarkers into standardised protocols.
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