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Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Michelakis ED, Webster L, Mackey JR. Br J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Review. PMID: 18766181 doi:10.1038/sj.bjc.6604554 The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg-1 day-1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study. Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity res

Simultaneously Blocking Glycolysis and Fat Metabolism Can the use of DCA and a fatty acid metabolism blocker together force more cancer cells into using aerobic metabolism? Tim McGough used green tea extract, which contains EGCG, in his fantastic response. DCA works by reactivating mitochondria and shifts metabolism from glycolysis to glucose oxidation. Hopefully the cancer cell will then undergo apoptosis. However, cancer cells have an alternate energy source: fat metabolism. This page explores to possibility of blocking fat metabolism to help force the cell into apoptosis. Oral squamous cell carcinoma is a cancer that does not respond well to DCA. This study, Head and Neck Cancer Cell Lines Are Resistant to Mitochondrial-Depolarization-Induced Apoptosis states: "Results: ΔΨm in head and neck cell lines started to show slight loss of ΔΨm, while HL-60 showed significant loss of ΔΨm after 30 min of treatment. All cell lines demonstrated complete mitochondrial depolarization within 24 h, however, only the control cell line HL-60 underwent apoptosis. In addition, HNSCC cell lines did not demonstrate cytoplasmic cytochrome c release despite significant mitochondrial membrane depolarization, while HL-60 cell initiated apoptosis and cytochcrome c release after 24 h of treatment. Conclusions: Head and neck cancer cell lines exhibit defects in mitochondrial-membrane-depolarization-induced apoptosis as well as impaired release of cytochrome c despite significant mitochondrial membrane depolarization. Proximal defects in the mitochondrial apoptosis pathway are a feature of HNSCC.(head and neck squamous cell carcinoma)" Note that although the cell lines were depolarized, apoptosis did not occur. So I checked to see if fatty acid metabolism is used by squamous cell carcinoma.

...has been the number one Google search term leading people to the blog this week - and that worries me. As I wrote about a week ago, dichloroacetate, or DCA, is the molecule tested recently by a team at University of Alberta for its ability to slow the growth of human lung cancer in immunocompromised rats. Among DCA's action is the ability to prevent cancer cells from producing lactic acid via aerobic glycolysis, a process used by more than half (but not all) tumors. Scientists continue to debate whether this process is a cause of cancer, or just a byproduct of malignant cell transformation. I am deeply concerned that desperate cancer patients may be trying to purchase dichloroacetate (DCA) and self-treat for cancer based on this highly-hyped single paper. To the credit of the researchers and their institution, who have set up a website to address the intense interest, they discourage such practice:

"Berberine is a quaternary ammonium salt from the group of isoquinoline alkaloids. It is found in such plants as Berberis, goldenseal (Hydrastis canadensis), and Coptis chinensis, usually in the roots, rhizomes, stems, and bark. Berberine is strongly yellow colored, which is why in earlier times berberis species were used to dye wool, leather and wood. Wool is still today dyed with berberine in Northern India Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome.[12] Berberine has been tested and used successfully in experimental[13] and human diabetes mellitus.[14][15][16] Berberine has been shown to lower elevated blood glucose as effectively as metformin.[17] The mechanisms include inhibition of aldose reductase,[18] inducing glycolysis,[19] preventing insulin resistance[20] through increasing insulin receptor expression[14] and acting like incretins. Berberine has drawn extensive attention towards its antineoplastic effects.[43][44] It seems to suppress the growth of a wide variety of tumor cells including breast cancer,[45] leukemia, melanoma,[46] epidermoid carcinoma, hepatoma, oral carcinoma, tongue carcinoma,[47] glioblastoma, prostate carcinoma, gastric carcinoma.[48][49] Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, tumor promotion, tumor invasion,[50][51][52][53][54] prostate cancer,[55][56][57][58] neuroblastoma,[59][60] and leukemia.[34][61] It is a radiosensitzer of tumor cells but not of normal cells

A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. Cancer Cell. 2007 Jan;11(1):37-51. PMID: 17222789 doi:10.1016/j.ccr.2006.10.020

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer.\nMichelakis ED, Webster L, Mackey JR.\nBr J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Review.\nPMID: 18766181 \ndoi:10.1038/sj.bjc.6604554 \n

You may have seen articles in the news about a drug called DCA (dichloroacetate), that is claimed to be cheap, safe and "kill most cancers". Understandably this has caused a great deal of interest, especially as DCA is an off-patent drug and appears to be non-toxic to humans. DCA has now been approved for a trial in brain cancer patients in Canada. The researchers have raised $800,000 in public donations to fund the trial

It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be