Dichloroacetate (DCA)

Transcription

1 Integrated Healthcare Practitioners Dietary and Nutritional Supplement, and Herbal Remedies Management Program Author: Christopher Habib, ND and Gurdev Parmar, ND, FABNO successful completion of the questions at the end of this paper has been approved for continuing education by the bddt-n; 1.0 credit nutritional medicine and by the cnpbc; one ce hour. Dichloroacetate (DCA) Application in cancer management Abstract Most cancer cells use anaerobic glycolysis for energy production, despite the fact that oxygen is present. This is termed the Warburg effect and results from mitochondrial dysfunction, which prevents mitochondria-based glucose oxidation. As a result, cancer cells upregulate glucose receptors and significantly increase glucose uptake, creating a large difference between malignant cells and normal cells. Glycolysis results in lactic acidosis and this can facilitate tumour growth by breaking down the extra-cellular matrix allowing for expansion, increasing cell mobility and metastatic potential, and by activating angiogenesis. Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and is a metabolite of industrial solvents. In this regard, it has been implicated in a variety of life-threatening toxicities and considered a human health hazard. However, DCA has been known for years to physicians and researchers as an investigational drug for certain metabolic diseases such as inborn errors of mitochondrial function in children, as well as a potentially promising therapy for cancer. DCA works by stimulating mitochondrial function and by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK). This activates pyruvate dehydrogenase (PDH) and at the expense of glycolysis, reverses the Warburg effect, diminishing the growth advantage of highly glycolytic tumours. DCA has been studied in multiple different formats: in vitro, in vivo, as monotherapy, and in conjunction with other drugs. It has shown signs of benefit in multiple cancers, including glioblastoma, ovarian cancer, endometrial cancer, breast cancer, lung cancer, colorectal cancer, and in metastatic carcinomas. The evidence available for DCA in the treatment of various cancers is reviewed. Clinical pearls from the practice of Gurdev Parmar, coauthor if this article and a Fellow of the American Board of Naturopathic Oncology are provided. Christopher Habib, ND Clinic Director Mahaya Forest Hill Warren Road Toronto, ON M4V 2R9 info@chrishabibnd.com Gurdev Parmar, ND, FABNO Integrated Health Clinic 2nd floor Mavis Ave Fort Langley, BC V1M2R4 info@integratedhealthclinic.com 80 IHP September 2012 } ihpmagazine.com IHP_CE2.indd :41 AM

2 Continuing Education Lesson Introduction Most cancer cells use anaerobic glycolysis for energy production, despite the fact that oxygen is present. This is termed the Warburg effect and results from mitochondrial dysfunction, which prevents mitochondria-based glucose oxidation (Bayley 2012). Since glucose oxidation is far more efficient at generating ATP compared with glycolysis, cancer cells upregulate glucose receptors and significantly increase glucose uptake. This creates a large difference between malignant cells and normal cells and offers the potential for a very selective therapeutic target, since glycolysis is not seen in normal tissue apart from skeletal muscle during strenuous exercise (Michelakis 2008). Glycolysis results in lactic acidosis, which has the ability to cause toxicity to surrounding tissues and to the cancer cells themselves. However, lactic acidosis can facilitate tumour growth by breaking down the extra-cellular matrix allowing for expansion, increasing cell mobility and metastatic potential, and by activating angiogenesis (Gatenby 2004). Thus, the metabolic remodeling in cancer cells that primarily utilize glycolysis may provide a survival advantage. Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and is a metabolite of industrial solvents (Stacpoole 2011). In this regard, it has been implicated in a variety of life-threatening toxicities and considered a human health hazard (IRAC 2004). However, DCA has been known for years to physicians and researchers as an investigational drug for certain metabolic diseases such as inborn errors of mitochondrial function in children, as well as a potentially promising therapy for cancer. DCA works by stimulating mitochondrial function and by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK) (Papandreou 2011). This activates pyruvate dehydrogenase (PDH) and at the expense of glycolysis, reverses the Warburg effect, diminishing the growth advantage of highly glycolytic tumours. DCA has been studied in multiple different formats: in vitro, in vivo, as monotherapy, and in conjunction with other drugs. It has shown signs of benefit in multiple cancers, including glioblastoma, ovarian, endometrial, breast, lung, colorectal, and in metastatic carcinomas (Michelakis 2008). This article will review the evidence available for DCA in the treatment of various cancers. Clinical pearls from the practice of Gurdev Parmar, coauthor of this article and a Fellow of the American Board of Naturopathic Oncology are also provided. ihpmagazine.com { September 2012 IHP IHP_CE2.indd 81

3 Continuing Education Lesson Mechanism of Action A metabolic modulator, DCA is a small molecule and when taken orally can achieve 100% bioavailability (Bonnet 2007). Due to its limited size, DCA can penetrate into the traditional chemotherapy sanctuary sites, including the brain (Michelakis 2008). In vitro, DCA activates PDH by inhibiting PDK and acts in a dose-dependent fashion. This results in a decrease of lactate levels in both the blood and the cerebrospinal fluid by more than 60% (Stacpoole 1989). The metabolic fate of glucose; either entry into glycolysis within the cell cytoplasm or oxidation within the mitochondria via the Kreb s cycle; is controlled by the gate-keeping mitochondrial enzyme, PDH. Thus, the activation of PDH shifts cell metabolism away from anaerobic glycolysis and towards glucose oxidation. The activation of PDH also causes numerous other anti-cancer effects within the cell. DCA has an effect on the polarization of the mitochondrial membrane, due to the enhanced activity of PDH. Several human cancer cells have high mitochondrial membrane potential, including non-small cell lung cancer, breast cancer, and glioblastoma cell lines, when compared with non-cancer cell lines (Bonnet 2007). By decreasing the polarization potential, DCA causes an opening of mitochondrial transition pores. This allows the movement of reactive oxygen species, such as hydrogen peroxide, and cytochrome c from the mitochondria to the cytoplasm of the cell, inducing apoptosis through the activation of caspases (Seth 2011). Neoplastic cell lines also express a lower level of potassium channels, which contributes to apoptosis resistance. The mitochondrial remodeling that occurs due to DCA has another downstream effect, since mitochondria also control calcium concentrations and calcium and potassium concentrations are related. DCA upregulates and actives potassium channels in cancer cells, but not in normal cells. This inhibits tumour growth without causing toxicity (Bonnet 2007). The initial half-life with the first dose of DCA is less than an hour, but this half-life increases to several hours with subsequent doses. With chronic use, serum levels plateau (Mori 2004). In clinical trials for lactic acidosis, sepsis, burns, and cirrhosis, doses have ranged from 25 to 100mg/kg per day orally or intravenously (Stacpoole 2003). Evidence DCA has been studied for the treatment of glioblastomas (GBM). In GBM cell lines from 49 patients, DCA reversed mitochondrial hyperpolarization and did not affect the polarization of normal brain tissue (Michelakis 2010). Five consecutive patients with primary GBM were also treated with DCA. Three of these patients had recurrent GBM with disease progression after several chemotherapies and standard treatment, and thus were considered appropriate for palliative therapy. The remaining two patients were newly diagnosed after debulking surgery and DCA was administered in addition to standard treatment. Patients were treated with a starting dose of 12.5mg/kg orally twice a day for 1 month, at which point the dose was increased to 25mg/kg orally twice a day. Following this, a dose de-escalation protocol was initiated, whereby the dose was decreased by 50% when dose-limiting toxicity occurred. The patients were followed for 15 months. None had hematologic, hepatic, renal, or cardiac toxicity. Peripheral neuropathy was the only apparent toxicity and it resolved when the dose was decreased to 6.25mg/kg orally twice a day. Three of the patients showed evidence of radiologic regression on MRI. Four of the patients were clinically stable at month 15 of DCA therapy and alive at month 18 (Michelakis 2010). In one study examining the use of DCA on ovarian cancer cell lines, the researchers utilized mitaplatin, a compound with two DCA units appended to a platinum center that when reduced also releases cisplatin, a common chemotherapy drug (Dhar 2009). Platinum compounds are used in half of all cancer therapies (Galanski 2005). However, the use of cisplatin to treat malignancies has been limited because of side effects and acquired resistance, which is a failure to execute apoptosis despite initiation of the apoptotic cascade (Siddik 2003). The combination of cisplatin and DCA provides a dual killing mechanism. Through this unique mechanism, mitaplatin attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. A separate study examined the use of DCA alone on epithelial ovarian cancer cells. These cancer cells are under intrinsic oxidative stress that alters metabolic activity and reduces apoptosis. DCA was able to reverse the increased oxidative stress and induce apoptosis (Saed 2011). A study of DCA on endometrial cell lines showed that DCA treatment initiated apoptosis in five low to moderately invasive cancer cell lines and had no effect on a non-cancerous cell line (Wong 2008). Two highly invasive endometrial adenocarcinoma cell lines were found to be resistant to DCA-induced apoptosis. Thus, DCA does not have evidence of efficacy in some cancer types. Tumour acidity is a driving force in invasion and metastases and the buffering of extracellular acidity can inhibit the spread of metastases. This was shown in a mouse model for metastatic breast cancer (Robey 2011). In this study, DCA alone or in 82 IHP September 2012 } ihpmagazine.com IHP_CE2.indd 82

4 combination with bicarbonate did not increase systemic alkalosis. DCA monotherapy was not effective in reducing tumour size or metastases or improving survival time. This outcome may be a function of hypoxia in the tumour microenvironment (Robey 2011). However, in another study of breast cancer cells, DCA was studied in combination with arsenic trioxide, a drug that is typically used in promyeloid leukemia (Sun 2011). The combination of the drugs was more effective at inhibiting cell proliferation and inducing cell death than either drug alone. A recent study examining lung carcinoid cell lines utilized DCA in combination with other platinum-based chemotherapeutic drugs, including satraplatin and picoplatin (Fiebiger 2011). The carcinoid cell lines were sensitive to the majority of chemotherapeutics in vitro. Even in highly chemoresistant cell lines, DCA was able to inhibit their growth by 22% and sensitized the cells to some of the platinum-based drugs (Fiebiger 2011). In a study of colorectal cancer cells, DCA was tested alone and in combination with 5-Fluorouracil (5-FU), the classical chemotherapy agent that has been the first line regimen for treating colorectal cancer (Meyerhardt 2005). Four human cell lines were treated in total. Cell cycle and apoptosis were measured by flow cytometry and the expression of apoptosisrelated molecules was assessed by western blot. The results showed that DCA inhibited the viability of colorectal cancer cells and had a synergistic anti-proliferation effect in combination with 5-FU (Tong 2011). Therefore, DCA appears to be helpful when used in combination with other chemotherapy drugs. Finally, a recent case report has investigated the use of DCA for cancer treatment in a palliative setting (Khan 2011). A 71-year-old male with poorly differentiated carcinoma of unknown primary metastatic origin to the right leg and liver achieved excellent palliation of leg pain by using oral DCA after failing conventional therapy (Khan 2011). This patient was treated with 500mg three times a day (the equivalent of 21mg/kg) on a 2 week on and 1 week off cycle. After 8 months, the patient was able to eliminate the use of opiates, including morphine, and did not experience any side effects from DCA treatment. To help prevent peripheral neuropathy, the patient was simultaneously treated with R+ alpha lipoic acid (ALA), acetyl L-carnitine, and benfotiamine (Khan 2011). These additional therapies may be useful for patients undergoing DCA therapy. Clinical Pearls Dr. Gurdev Parmar, ND, FABNO is the founder and medical director of the Integrated Health Clinic in Fort Langley, British Columbia. Dr. Parmar has been supervising patient s using oral DCA for several years, and has now used it in well over a hundred patients. Patients are typically started at 15mg/kg/day in divided doses, either 2 weeks on and 1 week off, or 5 days on and 2 days off. In Dr. Parmar s opinion, the break is critical for limiting the only known significant side effect of reversible peripheral neuropathy. The dose is then titrated up to 40-50mg/kg/day, by increments of 7.5mg/kg/day every 1-3 months, depending on the patient s Karnofsky score and co-morbidities. Dr. Parmar rarely exceeds an oral dose of 45 to 50 mg/kg/day. Dr. Parmar has also used IV DCA for the past year, and has treated approximately 30 patients with the IV form of DCA. The starting dose used was 20mg/kg per IV, once to twice weekly. Many patients were escalated up to 50mg/kg per IV once to twice weekly. In conjunction with this treatment, IV ALA and Intravenous Vitamin C are administered. In addition, an oral supplement regime of ALA, acetyl-l-carnitine, and vitamin B1 are recommended to help limit neuropathy, and doubled to treat it if it does occur. When patients develop neuropathy, they are asked to stop DCA treatment altogether until symptoms start to improve. At that point, they are started at 7.5mg/kd/day and slowly titrated to the highest tolerated dose, not to exceed the dose that previously caused the neuropathy. In terms of side effects that have been noted, Dr. Parmar has had one patient develop motor and sensory, seemingly central nervous system related symptoms. This patient developed symptoms including confusion, twitching, fatigue and muscle weakness. This occurred in the absence of any peripheral neuropathy in the hands and feet, and at a dose of 47 mg/kg/day. This patient was however also receiving several adjunctive therapies concurrently to the DCA, which included herbs that could have induced the drug, or down-regulated its metabolism and excretion. In fact, he was taking over 30 different herbal preparations previously prescribed by a herbalist, including very high doses of artemisinin, a known neurotoxic agent (Schmuck 2002). Dr. Parmar has had several patients that have had a significant response to DCA, with partial to complete responses on imaging, due to DCA monotherapy. One patient with stage IV colorectal cancer who was no longer receiving conventional therapy due to lack of benefit, had no evidence of disease after almost a year of DCA therapy. Another colorectal cancer patient was rapidly metastasizing prior to DCA therapy. For two years since she initiated DCA therapy, her disease has been stable. Finally, several patients with GBM have received Continuing Education Lesson ihpmagazine.com { September 2012 IHP IHP_CE2.indd 83

5 Continuing Education Lesson DCA alongside local-regional hyperthermia, which has led to significant improvements on repeated MRI and contrast CT. Dr. Parmar s Integrated Health Clinic is currently working to collate this information on a database, with plans for publication thereafter. He is particularly interested in the tumour microenvironment, and the positive metabolic and immunogenic effects of hyperthermia alongside novel treatments such as DCA. Conclusion After many years of use, the only documented side effect of DCA is dose-dependent reversible peripheral neuropathy (Michelakis 2008). DCA activates PDH and shifts the metabolism of cancer cells towards glucose oxidation. In addition, DCA decreases the polarization potential of the mitochondria, causing an opening of mitochondrial transition pores and leading to apoptosis. There is direct preclinical evidence of anticancer effects of References Bayley JP, Devilee P. The Warburg effect in Curr Opin Oncol. 2012;24(1): Bonnet S, Archer SL, Allalunis-Turner J, Jaromy 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. A mitochondria-k+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11(1): Chen LB. Mitochondrial membrane potential in living cells. Annu Rev Cell Biol. 1988;4: Dhar S, Lippard SJ. Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A. 2009;106(52): Fiebiger W, Olszewski U, Ulsperger E, Geissler K, Hamilton G. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Transl Oncol. 2011;13(1): Galanski M, Jakupec MA, Keppler BK. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem. 2005;12(18): Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11): IARC (International Agency for Research on Cancer). Dichloroacetic acid. IARC Monogr Eval Carcinog Risks Hum. 2004;84: Khan A. Use of oral dichloroacetate for palliation of leg pain arising from metastatic poorly differentiated carcinoma: a case report. J Palliat Med. 2011;14(8): Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008; 99(7): DCA with glioblastoma, ovarian, endometrial, breast, lung, and colorectal cancer. Though DCA appears more effective in combination with other chemotherapy drugs, it is not effective in all cell lines. The lack of mitochondrial hyperpolarization in certain types of cancer including lymphomas, neuroblastomas, and sarcomas indicates that DCA may not be effective in these cases (Chen 1988). There is limited evidence for the direct use of DCA in human patients, but funding for trials is a challenge since DCA is a generic drug and industry support may be limited. DCA treatment is still considered experimental is not endorsed by the authors. DCA therapy should only be used as an adjunct to current best practices and does not replace standard of care. Clinical experiences from the practice of a Fellow of the American Board of Naturopathic Oncology support the general safety and efficacy of the supervision of patients wanting to receive the experimental treatment of DCA, both orally and intravenously. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352(5): Papandreou I, Goliasova T, Denko NC. Anticancer drugs that target metabolism: Is dichloroacetate a new paradigm? Int J Cancer. 2011;128(5): Robey IF, Martin NK. Bicorbonate and dichloroacetate: evaluating ph altering therapies in a mouse model for metastatic breast cancer. BMC Cancer. 2011;11:235. Saed GM, Fletcher NM, Jiang ZL, Abu-Soud HM, Diamond MP. Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci. 2011;18(12): Schmuck, G, Roehrdanz E, Haynes RK, Kahl R. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother. 2002; 46(3): Seth P, Grant A, Tang J, Vinogradov E, Wang X, Lenkinski R, Sukhatme P. Ontarget Inhibition of Tumor Fermentative Glycolysis as Visualized by Hyperpolarized Pyruvate. Neoplasia. 2011; 13(1): Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47): Stacpoole PW. The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither? Environ Health Perspect. 2011;119(2): Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989;38(11): Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactatelowering drug. J Clinc Pharmacol. 2003;43(7): Sun RC, Board PG, Blackburn AC. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells. Mol Cancer. 2011;10:142. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurty MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2(31):31ra34. Mori M, Yamagata T, Goto T, Saito S, Momoi MY. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev. 2004;26(7): Tong J, Xie G, He J, Li J, Pan F, Liang H. Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer. J Biomed Biotechnol. 1011; Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I. Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol. 2008;109(3): IHP September 2012 } ihpmagazine.com IHP_CE2.indd 84

6 Questions 1. The Warburg effect refers to which of the following phenomena: a) most cancer cells use anaerobic glycolysis for energy production despite the fact that oxygen is present b) most cancer cells use glucose oxidation (Kreb s cycle) for energy production because oxygen is present c) cancer cells elevated metabolism utilizes available glucose in the environment, effectively starving normal cells 2. Which of the following is true about the uses of DCA? a) DCA is a by-product of water chlorination and a metabolite of industrial solvents b) DCA is a considered a human health hazard by the IARC c) DCA improves mitochondrial function, so has been used as an investigational drug for certain inborn errors of mitochondrial function in children 3. Which of the following describes the mechanism by which DCA works? a) DCA inhibits the regulatory pyruvate dehydrogenase kinases (PDK) and activates pyruvate dehydrogenase (PDH), which upregulates the Kreb s cycle b) DCA inhibits glycolysis and reverses the Warburg effect, c) DCA diminishes the growth advantage of highly glycolytic tumours 4. DCA has been found to reduce lactic acid in the blood and CSF by up to 90%. 5. DCA exerts pro-apoptotic effects by reducing mitochondrial membrane hyperpolarization, and thereby increasing the permeability of the mitochondrial membrane to reactive oxygen species; these signal for apoptosis when they are present in the cytosol. 6. In a report of 5 patients with glioblastoma, treatment with DCA resulted in: a) significant cardiac toxicity b) tumor regression in 3 patients on MRI c) disease stabilization in all 5 patients 7. In vitro studies suggest that DCA may be able to reverse resistance to cisplatin chemotherapy. 8. A case report of a patient with advanced metastatic cancer who had failed conventional therapy found that DCA was able to: a) induce complete regression of the tumor b) provide palliation resulting in elimination of the need for opiates c) improve survival 9. Clinically, Dr Parmar utilizes an on-off protocol to limit development of reversible peripheral neuropathy: patients are typically started at 15mg/kg/day in divided doses, either 2 weeks on and 1 week off, or 5 days on and 2 days off, and rarely exceed an oral dose of 45 to 50 mg/kg/day. 10. Which of the following combination of nutritional agents is used to help prevent the development of peripheral neuropathy alongside DCA? a) Benfotamine, methylcobalamin, and folic acid b) Benfotamine, melatonin, and acetyl-l-carnitine c) Benfotamine, alpha lipoic acid, and actyl-l-carnitine d) Benfotamine, alpha lipoic acid, and methylcobalamin Continuing Education Lesson Fax or answers to: or philip@ihpmagazine.com Name: Address: City: Province: Postal Code: Phone: Practice Registration #: Size of Practice (# of Doctors): Fax: Area of Clinical Focus: & up Years of Practice: & up ihpmagazine.com { September 2012 IHP IHP_CE2.indd 85