DCA
Updated: 17 hours ago
Anyone who does research on cancer treatments will run across Sodium Dicloroacetate. This tiny molecule has been around since before the turn of the last century and has some very interesting properties.
Reversing the Warburg effect through Metabolic Modulation
There are multiple parallel ways by which metabolism (a glycolic environment) induces and regulates a mitochondrial remodeling (hyperpolorization) that is associated with decreased levels of AOS and inhibited Kv channels, all prompting resistance to apoptosis. DCA has been found to facilitate oxidation of lactate via increase in activity of pyruvate dehydrogenase and thereby inhibit PDK.
Before your eyes glaze over and your mind becomes numb after reading last two sentences just remember that studies suggest that DCA inhibits tumor growth and may decrease proliferation and induce apoptosis in cancer cell lines. It is definitely worth working through a little of the "technical" information, especially if you're going to ask your doctor to prescribe it for you.
(taken from New Scientist Health Update, 16 May 2011)
To understand how DCA works you need a little working knowledge of how the mitochondria works. You will read that it is the "power plant" of the cell and it is, but it much more complicated than just nutrients going in and energy going out, It is voltage sensitive and positive and negative ions pass through the membrane that encompasses it. The more neutrally charged it is the healthier it is and balanced levels of ions can pass through the membrane wall carrying metabolites such as Pyruvate and fatty acids. Though they don't understand completely how this works, it seems that cancer with it's fermentation environment inhibits VDAC (voltage dependent anion (negatively charged ion channels) which decreases levels of Oxygen (ASO) and potassium (K+) channels into the mitochondria. This hyperpolorizes the mitochondria (makes it very negatively charged) and prevents the movement of anions down an electrical gradient increasing intra-mitochondrial anions. What is surprising is that though this has been known for almost 35 years, it has not been linked to apoptosis resistance in cancer.
Since the 1980s Dr. Chen at the Dana Farber Institute has shown that cancer cells have hyperpolorized mitochondria as compared with noncancerous cells. He studied 200 cell lines/types derived from tumors of kidney, ovary, pancreas, lung, adrenal cortex, skin, breast, prostate, cervix, vulva, colon, liver, testis, esophagus, trachea and tongue. The results of this six year study "overwhelmingly indicated that all normal epithelial cells tested have low mitochondrial membrane potential (balanced electrical charge), and that a great majority of adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma melanoma have high mitochondrial membrane potential (very negatively charged). He made these observations using a positively charged dye (rhodamine 123) used to study mitochondrial membrane potential (which just sucked up the positively charged dye).
A glycolic environment is associated with an antiapoptopic and pro-proliferative state, characterizing most solid tumors. Increased entry of pyruvate into the mitochondria by either DCA or inhibition of LDH promotes glucose oxidation, increased apoptosis, and decrease proliferation and tumor growth.
Dr. Peter Pedersen and his students at Johns Hopkins have found that HK2(HexoKinase 2 which causes Warburg effect) binds with the tumor Mitochondria and uses the VDAC protein to be come immortal. (This lecture is more for someone who has a biomedical background such as your doctor, but if you can stay awake without rolling your eyes into the back of your head, this is worth viewing.) We can see 95% of cancers because they are PET positive (they are sugar hogs and light up a PET scan).
DCA depolarizes the cancer mitochondria by returning the membrane potential (it's charge) to that of normal cells without affecting the mitochondria of non cancerous cells. Remarkably all of the above features of the cancer cells were "normalized" following the mitochondrial depolarization. The fact that GO(energy production that only occurs inside the mitochondria) was increased by DCA clearly shows that cancer mitochondria are functional and not irreversibly damaged as previously thought. This further raises the intriguing possibility that in cancer there is an active and dynamic suppression of mitochondrial function in order to also suppress apoptosis. "Refueling" of the mitochondria with DCA reverses this suppression, reactivates the apoptopic machinery and unlocks the cancer cell from a state of apoptosis resistance.
Below is the "technical" explanation of the process to take to your doctor.
This is an easy to understand article on how DCA works.
Though I was aware of DCA from the first days of my diagnosis. My problem wasn't that the FDA has made a concentrated effort over the years to give it a bad name and to take it away from the general public but the fact that it causes dose-dependent, reversible peripheral neuropathy (a numbing sensation in the extremities). It was unknown if this side effect would become permanent and irreversible with continued use, so what was the right dose? That question was answered by Evangelos Michelakis of the University of Alberta in his:
"We treated patients with a starting dose of 12.5 mg/kg orally twice a day for 1 month, at which point the dose was increased to 25mg/kg orally twice a day. We then followed a dose de-escalation protocol, decreasing the dose by 50% when dose-limiting toxicity occurred. The patients were followed clinically for up to 15 months. None of the patients had hematologic, hepatic, renal, or cardiac toxicity. Peripheral neuropathy was the only apparent toxicity. Patients had variable dose-dependent degrees of peripheral neuropathy, which was reversible, confirming previous studies. When the dose was decreased to 6.25 mg/kg orally twice a day, none of the patients had clinically significant peripheral neuropathy. Initially, the half-life of DCA is <1 hour. DCA inhibits its own metabolism and serum concentrations increase, eventually reaching a plateau. The plasma trough concentrations of DCA in our patients remained undetectable for the first 2 to 3 months but thereafter reached therapeutic concentrations. At a dose of 6.25 mg/kg orally twice a day for at least 3 months, trough DCA concentrations were 0.44 ±."
His (Phase one) trial to test for effective dosing came up with 6.25mg/k twice a day and efficacy occurred at 2 to 3 months. I weigh 108lb. That divided by 2.2 to find my weight in Kilos is 49k. Multiply 49 x 6.25 = 306.8 mg (I take 307mg) twice a day. With that I take Thiamine (B1) twice a day. (Do not use Benfotiamine a synthetic B1 as it metabolizes like glutamine and might feed the cancer.) I find that 450mg taken twice a day with the DCA prevents any peripheral neuropathy. Since Thiamine is a water soluble vitamin I have read of people taking 1000mg a day without any problems.
Warning: Caffeine enhances the efficacy of DCA and high doses of DCA and Caffeine have caused some serious complications. The most serious of these is Tumor Lysis Syndrome – a toxic collateral burden imposed on the body from the simultaneous death and release of malignant shrapnel into the bloodstream. (Since Caffeine interferes with the efficacy of metformins ability to inhibit Her2/neu I don't use it. Though I do still eat small daily amounts of homemade sugarless chocolate and drink decaf coffee which contains slight amounts of caffeine.)
The site below is not medical. It's more a links and lay research on DCA. I found it helpful, you might as well.
The top sites supplying NaDCA to the public are:
and www.puredca.com
The cost is from $2 to $4 a day.
I buy mine from www.certifieddca.com simply because each batch is tested in Canada for purity and any solvents or heavy metals. They also send you a certificate of analysis once you have ordered. It is a little more expensive, about 20-40 cents more per day.
References for DCA
Stacpoole PW. The pharmacology of dicholoracetate. Metabolism. 1989; 38:1124-1144.
Stacpoole PW, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006; 117:1519-1531.
Bonnet S, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11:37-51. http://ac.els-cdn.com/S1535610806003722/1-s2.0-S1535610806003722-main.pdf?_tid=c33887e6-88c9-11e2-bdf8-00000aacb35e&acdnat=1362841272_9f84bf3bb5e9144c92009d7192328638
Sutendra G, et al. Mitochondrial activation by inhibition of PDKII suppressers HIF1a signaling and angiogenenisis in cancer. Oncogene. 2012 May 21. doi: 10.1038/onc.2012.198. [Epub ahead of print]
Kamb A, Wee S, Lengauer C. Why is cancer drug discovery so difficult? Nat Rev Drug Discov. 2007; 6:115-120.
Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. British J Cancer. 2008; 99:989-994.
Cornett R, et al. Inhibition of glutathione S-transferase zeta and tyrosine metabolism by dichloroacetate: a potential unifying mechanism for its altered biotransformation and toxicity. Biochem Biophys Res Commun. 1999; 262(3):752-6.
Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994; 269:23757-23763.
Warbug O. Uber den stoffwechsel der tumoren. Constable: London.
Gatenby RA; Gillies RJ. Why do cancers have high aerobic glycolysis? Nature Reviews Cancer. 2004; 4(11).
Kim JW, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3:177-185. http://mcb.asm.org/content/27/21/7381.short
Zamzami N. Kroemer G. The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol. 2001; 2:67-71.
Pan JG, Mak TW. Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE. 2007; 381:pe14.
Michelakis ED, Sutendra G, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010; 2(31):31ra34.
Madhok BM, et al. Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. British J Cancer. 2010; 102:1746-1752. http://www.nature.com/bjc/journal/v102/n12/full/6605701a.html
Ying-Chun S, Hsiang-Hsuan F, et al. Abstract B97: Dichloroacetate (DCA) enhances activities of sorafenib against hepatocellular carcinoma (HCC) via modulation of aberrant cellular metabolism of HCC cells. Mol Cancer Ther. 2009; 8(12) Supplement 1.Dichloroacetate (DCA) enhances activities of sorafenib against hepatocellular carcinoma (HCC) via modulation of aberrant cellular metabolism of HCC cells. Mol Cancer Ther. 2009
Ramon CS, Mitali F, et al. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2009; 120(1):253-60.
Sun RC, Board PG, Blackburn AC. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells. Mol Cancer. 2011; 10:142.
Stander XX, et al. In vitro effects of an in silico-modelled 17β-estradiol derivative in combination with dichloroacetic acid on MCF-7 and MCF-12A cells. Cell Prolif. 2011; 44(6):5567-81.
Khan, A. Medicor Cancer Clinic: Dec 2007 DCA Efficacy Report http://www.thedcasite.com/Library/Use_of_Oral_Dichloroacetate_for_Palliation_of_Leg_Pain_Arising_from_Metastatic_Poorly_Differentiated.pdf
Ishiguro T, Ishiguro R, et al. Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. Hepatogastroenterology. 2012; 59(116):994-6.
Khan, A. Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate. Advances in Cancer: Research & Treatment. 2012; 2012, Article ID 441895, 7. http://www.ibimapublishing.com/journals/ACRT/2012/441895/441895.pdf
Strum SB, Adalsteinsson O, et al. Case Report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s Lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr. 2012 Dec 20. [Epub ahead of print]
Wong JY, Huggins GS, et al. Dichloroacetate induces apoptosis in endometrial cancer cells. Gyne Oncology. 2008; 109(3):394-402.
Cao W, Yacoub S, et al. Dichloroacetate (DCA) sentizes both wild-type and overexpressing Bcl-2 proatate cancer cells in vitro to radiation. Prostate. 2008; 68(11):1223-1231.
Saed GM, Fletcher NM, et al. Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci. 2011; 18(12):1253-61.
Vella S, Conti M, et al. Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. Int J Cancer. 2012; 130(7):1484-93. http://onlinelibrary.wiley.com/doi/10.1002/ijc.26173/full
Fiebiger W, Olszewski U, et al. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Tranl Oncol. 2011; 13(1):43-9. http://link.springer.com/article/10.1007/s12094-011-0615-z
Pauly DF, Pepine CJ. Ischemic heart disease: metabolic approaches to management. Clin Cardiol. 2004; (27)8:439-41. http://www.heartandmetabolism.com/download/36/7.pdf
Piao L, Fang YH, et al. The inhibition of pyruvate dehyrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl). 2010; 88(1):47-60.http://www.ncbi.nlm.nih.gov/pubmed/19949938
Stacpoole PW, Henderson GN, et al. Pharmacokinetics, metabolism and toxicology of dichloroacetate. Drug Metab Rev. 1998; 30(3):449-539. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533324/
References for DCA
Stacpoole PW. The pharmacology of dicholoracetate. Metabolism. 1989; 38:1124-1144.
Stacpoole PW, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006; 117:1519-1531.
Bonnet S, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11:37-51. http://ac.els-cdn.com/S1535610806003722/1-s2.0-S1535610806003722-main.pdf?_tid=c33887e6-88c9-11e2-bdf8-00000aacb35e&acdnat=1362841272_9f84bf3bb5e9144c92009d7192328638
Sutendra G, et al. Mitochondrial activation by inhibition of PDKII suppressers HIF1a signaling and angiogenenisis in cancer. Oncogene. 2012 May 21. doi: 10.1038/onc.2012.198. [Epub ahead of print]
Kamb A, Wee S, Lengauer C. Why is cancer drug discovery so difficult? Nat Rev Drug Discov. 2007; 6:115-120.
Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. British J Cancer. 2008; 99:989-994.
Cornett R, et al. Inhibition of glutathione S-transferase zeta and tyrosine metabolism by dichloroacetate: a potential unifying mechanism for its altered biotransformation and toxicity. Biochem Biophys Res Commun. 1999; 262(3):752-6.
8. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994; 269:23757-23763.
Warbug O. Uber den stoffwechsel der tumoren. Constable: London.
Gatenby RA; Gillies RJ. Why do cancers have high aerobic glycolysis? Nature Reviews Cancer. 2004; 4(11).
Kim JW, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3:177-185.
Zamzami N. Kroemer G. The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol. 2001; 2:67-71.
Pan JG, Mak TW. Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE. 2007; 381:pe14.
Michelakis ED, Sutendra G, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010; 2(31):31ra34.
Madhok BM, et al. Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. British J Cancer. 2010; 102:1746-1752. http://www.nature.com/bjc/journal/v102/n12/full/6605701a.html
Ying-Chun S, Hsiang-Hsuan F, et al. Abstract B97: Dichloroacetate (DCA) enhances activities of sorafenib against hepatocellular carcinoma (HCC) via modulation of aberrant cellular metabolism of HCC cells. Mol Cancer Ther. 2009; 8(12) Supplement 1. http://mct.aacrjournals.org/cgi/content/meeting_abstract/8/12_MeetingAbstracts/B97
Ramon CS, Mitali F, et al. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2009; 120(1):253-60.
Sun RC, Board PG, Blackburn AC. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells. Mol Cancer. 2011; 10:142.
Stander XX, et al. In vitro effects of an in silico-modelled 17β-estradiol derivative in combination with dichloroacetic acid on MCF-7 and MCF-12A cells. Cell Prolif. 2011; 44(6):5567-81.
Khan, A. Medicor Cancer Clinic: Dec 2007 DCA Efficacy Report http://www.medicorcancer.com/dca-data.html
Ishiguro T, Ishiguro R, et al. Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. Hepatogastroenterology. 2012; 59(116):994-6.
Khan, A. Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate. Advances in Cancer: Research & Treatment. 2012; 2012, Article ID 441895, 7. http://www.ibimapublishing.com/journals/ACRT/2012/441895/441895.pdf
Strum SB, Adalsteinsson O, et al. Case Report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s Lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr. 2012 Dec 20. [Epub ahead of print]
Wong JY, Huggins GS, et al. Dichloroacetate induces apoptosis in endometrial cancer cells. Gyne Oncology. 2008; 109(3):394-402.
Cao W, Yacoub S, et al. Dichloroacetate (DCA) sentizes both wild-type and overexpressing Bcl-2 proatate cancer cells in vitro to radiation. Prostate. 2008; 68(11):1223-1231.
Saed GM, Fletcher NM, et al. Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci. 2011; 18(12):1253-61.
Vella S, Conti M, et al. Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. Int J Cancer. 2012; 130(7):1484-93.
Fiebiger W, Olszewski U, et al. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Tranl Oncol. 2011; 13(1):43-9.
Pauly DF, Pepine CJ. Ischemic heart disease: metabolic approaches to management. Clin Cardiol. 2004; (27)8:439-41.
Piao L, Fang YH, et al. The inhibition of pyruvate dehyrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl). 2010; 88(1):47-60.
Stacpoole PW, Henderson GN, et al. Pharmacokinetics, metabolism and toxicology of dichloroacetate. Drug Metab Rev. 1998; 30(3):449-539.
Evangelos Michelakis of the University of Alberta
Evangelos Michelakis of the University of Alberta
Evangelos Michelakis of the University of Alberta
Evangelos Michelakis of the University of Alberta
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