1. Metabolic Therapy with DCA (dichloroacetate)
May 2014
Akbar Khan, M.D.

2. What is DCA? a by-product of water chlorination1 C2HCl2NaO2
dichloroacetic acid, sodium salt
small molecule, like “salt and vinegar”
highly water soluble
penetrates blood-brain barrier2
inhibits its own metabolism: GSTζ3
1. The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither?
Environ Health Perspect Feb;119(2): doi: /ehp Epub 2010 Oct 4.
2. Metabolic modulation of glioblastoma with dichloroacetate.
Sci Transl Med May 12;2(31):31ra34. doi: /scitranslmed
3. 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 Sep 7;262(3):752-6.

3. Mechanism of Action
inhibitor of PDH kinase (“PDK”) -> activates enzyme PDH resulting in a shift from glycolysis to glucose oxidation1
cancer: aerobic glycolysis “Warburg effect”
reduces mitochondrial membrane potential Δφm, triggering apoptosis1
(“natural cell suicide”)
other mechanisms being investigated2
1. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
Cancer Cell Jan;11(1):37-51.
2. Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer.
Oncogene May 21. doi: /onc [Epub ahead of print]

4. Mechanism of Action
DCA

5. Published in vitro Data
original Michelakis paper: non-small cell lung, breast, glioblastoma1
many others: colon2, prostate (alone and with radiation) 3, ovarian4, neuroblastoma5, lung carcinoid6, cervix7, endometrial8, gastric (with 5-FU) 9 , hepatocellular (with sorafenib) 10, head and neck SCC (with sulindac) 11, melanoma12, T-cell lymphoma13, sarcoma14 …
1. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
Cancer Cell Jan;11(1):37-51.
2. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate.
Oncogene Sep 22;30(38): doi: /onc Epub 2011 Apr 18.
3. Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.
Prostate Aug 1;68(11): doi: /pros
4. Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress.
Reprod Sci Dec;18(12): doi: / Epub 2011 Jun 23.
5. Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells.
Int J Cancer Apr 1;130(7): doi: /ijc Epub 2011 Aug 27.
6. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines.
Clin Transl Oncol Jan;13(1):43-9. doi: /s z.
7. Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells.
Int J Oncol Feb;38(2): doi: /ijo Epub 2010 Dec 3.
8. Dichloroacetate induces apoptosis in endometrial cancer cells.
Gynecol Oncol Jun;109(3): doi: /j.ygyno Epub 2008 Apr 18
9. Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target.
Int J Oncol Jan;42(1): doi: /ijo Epub 2012 Nov 6.
10. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma.
Br J Cancer Jan 15;108(1): doi: /bjc Epub 2012 Dec 20.
11. Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage.
PLoS One. 2012;7(7):e doi: /journal.pone Epub 2012 Jul 17.
12. Inactivation of the HIF-1α/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants.
Cancer Res Oct 1;72(19): doi: / CAN Epub 2012 Aug 3.
13. Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation.
Chem Biol Interact Jul 30;199(1): doi: /j.cbi Epub 2012 Jun 15.
14. The influence of sodium dichloroacetate on the oxidative processes in sarcoma 37.
Exp Oncol Dec;33(4):

6. Un-published in vitro Data1
potential strong synergism with metformin in breast ca + others (breast confirmed in vivo)
potential strong synergism with erlotinib in non-small cell lung ca (confirmed in vivo)
potential strong synergism with taxane, platinum + other chemos (platin. conf. in vivo)
potential antagonism of chemos2
-> unpredictable, need CS/CR assay
1. internal Medicor data from ChemoFit live cell CS/CR assay LAST ACCESSED JAN 18, 2013
2. Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs
Cancer Chemother Pharmacol Mar;67(3): doi: /s Epub 2010 May 26.

7. Published in vivo Data
glioblastoma (tumour shrinkage in 2 patients treated with DCA alone)1
non-Hodgkins lymphoma (1 case of complete remission after chemo failure, DCA alone) 2
cholangiocarcinoma (1 case, response to DCA with omeprazole and tamoxifen) 3
unknown primary (dramatic pain reduction)*4
met renal SCC (cured by DCA + palliative XRT)*5
1. Metabolic modulation of glioblastoma with dichloroacetate.
Sci Transl Med May 12;2(31):31ra34. doi: /scitranslmed
2. 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 Dec 20. [Epub ahead of print]
3. Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report.
Hepatogastroenterology Jun;59(116): doi: /hge10507.
4. Use of oral dichloroacetate for palliation of leg pain arising from metastatic poorly differentiated carcinoma: a case report.
J Palliat Med Aug;14(8): doi: /jpm Epub 2011 Apr 12.
5. Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate
Advances in Cancer: Research & Treatment Vol (2012), Article ID , 7 pages DOI: /

8. Un-published in vivo Data
About 60% have partial response (palliation) in our experience1
Occasional complete remission (about 1/50 – 1/100)2
32 M, met. melanoma (CT proven P.R.)
50 F, GBM with Sx/XRT, chemo x 1 yr (C.R. > 2 yrs)
47 F, ovarian stage 4, + 3 doses carboplatin (C.R. x 2 yrs. then recurrence)
Current or past Medicor patients
Abbreviations: P.R.= partial response C.R.=complete response/remission, GBM=glioblastoma, XRT=radiation, Sx=surgery, TM=ammonium tetrathiomolybdate, cured=5 yr complete remission
Patients received alpha lipoic acid + benfotiamine + acetyl L-carnitine + other natural Rx with DCA

9. Un-published in vivo Data1
63 F, Non-Hodgkins Lymphoma (CT proven S.D.)
40 M, T-cell NHL w. CNS involvement (S.D. x 2 yrs)
44 M, angiosarcoma (S.D. x 1 yr)
10 M, pancreatic neuroendocrine (CT proven S.D.)
75 M, small cell lung (recur.) + 1 dose VP16 (cured)
Current or past Medicor patients
Abbreviations: S.D.= stable disease, TM=tetrathiomolybdate, POH=perillyl alcohol
Patients received alpha lipoic acid + benfotiamine + acetyl L-carnitine + other natural Rx with DCA

10. Un-published in vivo Data1
75 M, malig. fibrous histiocytoma (S.D. x 1.5 yrs)
80 M, TCC bladder (cysto proven shrinkage, cancelled radical cystectomy x 1 yr)
cholangiocarcinoma (S.D. and P.R. in several cases)
strong synergism with honokiol in CLL and others
strong synergism with fermented wheat germ extract in several cancers (AveUltraTM or AvemarTM)
PSA reduction in castration-resistant prostate ca
Current or past Medicor patients
Abbreviations: TCC=transitional cell carcinoma
honokiol used: HonoPure TM , FWGE used: AveUltra TM or Avemar TM
Patients received alpha lipoic acid + benfotiamine + acetyl L-carnitine + other natural Rx with DCA

11. Common Side Effects* Approx. 40% have no side effects
All reversible, incidence depends on dose
Neurological and G.I. primarily
Peripheral neuropathy ~20%
Fatigue / Sedation ~ 20%
Confusion/reduced memory ~20%
Tremors
* based on 2 cycles of oral DCA, 2wk on / 1wk off cycle, individual dose selection ~15-25mg/kg/d1
Medicor internal data

12. Side Effects Hallucinations Agitation
Mood changes – anxiety / depression
Heartburn
Nausea (rare vomiting)
Increased tumour pain (temporary)
Asymptomatic AST / ALT / GGT increase (1-2%)

13. Good Side Effects / Benefits
Safe in renal failure (liver metabol, no renal tox)
Good in angina & heart failure (↑ pumping efficiency with no ↑ in oxygen demand)1
Shortens QT interval (safe with ↑ QT drugs) 2
Improves diabetes (mild glucose ↓) 3
1. Ischemic heart disease: metabolic approaches to management.
Clin Cardiol Aug;27(8):
2. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle.
J Mol Med (Berl) Jan;88(1): doi: /s Epub 2009 Dec 1.
3. Pharmacokinetics, metabolism and toxicology of dichloroacetate.
Drug Metab Rev Aug;30(3):

14. Drug Interactions Minimal drug interactions in our experience1
Not metabolized by P450 system (GSTζ)
Caution with cannabinoids and other CNS drugs that cause delirium (start low, ↑ slowly)
1. There is very little published on interaction of DCA with other drugs

15. Need for Natural Medicines
↓ Side effects (neuropathy/encephalopathy):
R-alpha lipoic acid 150mg tid (avoid overlapping with XRT/chemo)
acetyl L-carnitine 500mg tid
benfotiamine (lipid sol vit B1) 80mg bid
Synergistic antineoplastic effects:
Dr. Neil McKinney ND, “mitochondrial rescue” 1
ALC, R-ALA, B1, Co-Q10, I3C, quercitin etc.
LAST ACCESSED JAN 18, 2013

16. Sample Protocol (oral)
DCA 15-25mg/kg/d, bid or tid, 14d on/7d off
R-ALA 150mg tid, benfotiamine 80mg bid, ALC 500mg tid
CBC, lytes, BUN, creat, Ca, albumin, bili (T+D), AST, ALT, ALKP, GGT, LDH, glucose, q 1 wk x 4 then reduce if ok
Relevant tumour marker(s) q 4 wks
If GI upset, try pantoprazole 40mg po qd

17. Protocols With Chemo
potential strong synergism with chemos, but also potential antagonism of chemos1
Protocol must be individualized along with specific chemo cycle
If CS/CR assay conducted, use appropriate combo per assay result
If no CS/CR assay, avoid overlapping DCA and chemo for safety (DCA between chemo doses)
internal Medicor data from ChemoFit live cell CS/CR assay
CS/CR = chemosensitivty / chemoresistance

18. Summary DCA may be effective for any cancer type
DCA may be effective for chemo-resistant cancers
DCA has no life-threatening side effects1, is not immunosuppressive, no effect on cell counts
DCA reduces its own metabolism (T½ increases)
Increasing side effects possible with stable dose
For oral DCA, cyclic therapy appears to be best)
1. When used under medical supervision with monitoring of liver enzymes

19. Summary Main limiting side effect is neuropathy
Natural neuropathy prevention is essential
if oral DCA causes side effects, DCA iv may be ok
Watch the liver enzymes
DCA works best in combination therapy (multi-targeted approach)
Palliative benefits are significant
Occ complete remission, stage 4 cancer (1-2%)1
1. Internal Medicor data, estimate based on % of patients with long term C.R. out of all patients treated with DCA.
Percentage of C.R. is actually higher when looking at only those treated with DCA + radiation and/or chemo.