Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer

Jingtao Tong, Ganfeng Xie, Jinxia He, Jianjun Li, Feng Pan, and Houjie Liang Department of Oncology, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Chongqing 400038, China Correspondence should be addressed to Houjie Liang, lianghoujie@sina.com Received 27 May 2010; Revised 29 December 2010; Accepted 13 January 2011 Academic Editor: Miguel A. Andrade Copyright © 2011 Jingtao Tong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been recently demonstrated as a promising nontoxic antineoplastic agent that promotes apoptosis of cancer cells. In the present study, we aimed to investigate the antitumor effect of DCA combined with 5-Fluorouracil (5-FU) on colorectal cancer (CRC) cells. Four human CRC cell lines were treated with DCA or 5-FU, or a combination of DCA and 5-FU. The cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide assay. The interaction between DCA and 5-FU was evaluated by the median effect principle. Immunocytochemistry with bromodeoxyuridine (BrdU) was carried out to determine the proliferation of CRC cells. Cell cycle and apoptosis were measured by flow cytometry, and the expression of apoptosis-related molecules was assessed by western blot. Our results demonstrated that DCA inhibited the viability of CRC cells and had synergistic antiproliferation in combination with 5-FU. Moreover, compared with 5-FU alone, the apoptosis of CRC cells treated with DCA and 5-FU was enhanced and demonstrated with the changes of Bcl-2, Bax, and caspase-3 proteins. Our results suggest that DCA has a synergistic antitumor effect with 5-FU on CRC cell lines in vitro. 1.  Introduction Colorectal cancer is one of the most common malignancies worldwide [1]. Other than surgery, treatment for CRC patients relies primarily on chemotherapy, especially the patients with advanced CRC. Among the chemotherapeutic agents for CRC, 5-Fluorouracil (5-FU), which is a classical chemotherapy agent, has been the first line regimen for treating CRC over several decades [2, 3]. However, 5-FU alone is poorly selective to tumor as well as highly toxic to bone marrow, gastrointestinal tract, and skin when used at the therapeutic dose [4]. Metabolic abnormity is one of the critical hallmarks of cancer [5]. As early as the 1920s, Otto Warburg observed that cancer cells generally use glycolysis rather than oxidative phosphorylation for energy [6]. Thus, the metabolic switch to anaerobic respiration through glycolysis from pyruvate, rather than pyruvate conversion to acetyl-CoA by the action of pyruvate dehydrogenase (PDH) in aerobic glucose metabolism, becomes a preferential phenotype of cancer progress. PDH can be inactivated by pyruvate dehydrogenase kinase (PDK) in many glycolytic phenotypes including cancer, while inhibition of PDK switches metabolism to aerobic oxidation which is proved to be disadvantageous to tumour growth [7]. Dichloroacetate (DCA) is a prototypical inhibitor of mitochondrial PDK. By blocking the enzyme, DCA decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. This property has led to trials…

Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate

Ellappan Babu, Ph. D, Sabarish Ramachandran, Ph. D, Veena CoothanKandaswamy, Ph. D., Selvakumar Elangovan, Ph. D, Puttur D. Prasad, Ph. D, Vadivel Ganapathy, Ph. D, and Muthusamy Thangaraju, Ph. D. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, USA Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence: M. Thangaraju, Ph. D., Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA., mthangaraju@georgiahealth.edu.Conflict of interest: The authors declare that there is no competing financial interest in relation to the work described in this manuscript.Published in final edited form as: Oncogene. 2011 September 22; 30(38): 4026–4037. doi:10.1038/onc.2011.113.Keywords: SLC5A8; dichloroacetate; anticancer drug; Warburg effect; pyruvate dehydrogenase kinase; mitochondrial oxidation in cancer Abstract There has been growing interest among the public and scientists in dichloroacetate as a potential anticancer drug. Credible evidence exists for the antitumor activity of this compound, but high concentrations are needed for significant therapeutic effect. Unfortunately, these high concentrations produce detrimental side effects involving nervous system, thereby precluding its use for cancer treatment. The mechanistic basis of the compound’s antitumor activity is its ability to activate pyruvate dehydrogenase complex through inhibition of pyruvate dehydrogenase kinase. Since the compound inhibits the kinase at micromolar concentrations, it is not known why therapeutically prohibitive high doses are needed for suppression of tumor growth. We hypothesized that lack of effective mechanisms for the entry of dichloroacetate into tumor cells may underlie this phenomenon. Here we show that SLC5A8 transports dichloroacetate very effectively with high affinity. This transporter is expressed in normal cells, but the expression is silenced in tumor cells via epigenetic mechanisms. The lack of the transporter makes tumor cells resistant to the antitumor activity of dichloroacetate. However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells, and prostate cancer cells. Normal cells, which constitutively express the transporter, are however not affected by the compound, indicating the tumor cell-selective therapeutic activity. The mechanism of the antitumor activity of the compound is still its ability to inhibit pyruvate dehydrogenase kinase and force mitochondrial oxidation of pyruvate. Since the silencing of SLC5A8 in tumors involves DNA methylation and its expression can be induced by treatment with DNA methylation inhibitors, our findings suggest that combining dichloroacetate with a DNA methylation inhibitor would offer a means to reduce the doses of dichloroacetate to avoid detrimental effects associated with high doses but without compromising antitumor activity. INTRODUCTION Dichloroacetate is currently used for the treatment of congenital lactic acidosis (Stacpoole et al., 2003, 2008). The therapeutic efficacy of this drug is due to its ability to activate pyruvate dehydrogenase complex (PDC) in mitochondrial matrix. However, the enzyme complex is not the direct target for the drug. Dichloroacetate is an inhibitor of pyruvate…

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

Stephen B. Strum & Örn Adalsteinsson & Richard R. Black & Dmitri Segal & Nancy L. Peress & James Waldenfels S. B. StrumInternational Strategic Cancer Alliance, 538 Granite Street, Ashland, OR 97520, USAe-mail: sbstrum@gmail.comS. B. StrumAmerican Society of Clinical Oncology, 538 Granite Street, Ashland, OR 97520, USAS. B. StrumAmerican Urological Association, 538 Granite Street, Ashland, OR 97520, USAÖ. AdalsteinssonInternational Strategic Cancer Alliance, 873 E. Baltimore Pike #333, Kennett Square, PA 19348, USAe-mail: ornaa@comcast.netR. R. BlackNuclear Medicine and PET Imaging, Radisphere Teleradiology Group, Beachwood, OH 44022, USAe-mail: drrickblack@aol.comD. SegalValley Radiology Consultants, Poway, CA 92064, USAe-mail: dmitrisegal@gmail.comN. L. PeressLife Extension Foundation, 5760 S. Scenic Drive, Sault Sainte Marie, MI 49783, USAe-mail: nperess@charter.netJ. WaldenfelsLife Extension Foundation, 9114 Steeplebush Court, Annandale, VA 22003-4051, USAe-mail: luckyodie2@aol.com Keywords: Dichloroacetate . DCA . non-Hodgkin’s lymphoma . NHL . PET . PET/CT . Glycolysis . Metabolomics . WarburgAbbreviations: DCA (dichloroacetate)NHL (non-Hodgkin’s lymphoma)PET (Positron Emission Tomography)CT (computerized tomography)FDG (fluorodeoxyglucose)SUV (standardized uptake value)mg (milligrams)kg (kilograms)R-CHOP (rituximab-Cytoxan,Hydroxydaunomycin, Oncovin, Prednisone) Received: 27 October 2012 Accepted: 23 November 2012Springer Science+Business Media New York 2012 Abstract The uptake of fluorodeoxyglucose Positron Emission Tomography in the tumors of various cancer types demonstrates the key role of glucose in the proliferation of cancer. Dichloroacetate is a 2-carbon molecule having crucial biologic activity in altering the metabolic breakdown of glucose to lactic acid. Human cell line studies show that dichloroacetate switches alter the metabolomics of the cancer cell from one of glycolysis to oxidative phosphorylation, and in doing so restore mitochondrial functions that trigger apoptosis of the cancer cell. Reports of dichloroacetate in human subjects are rare. The authors contacted individuals from Internet forums who had reported outstanding anti-cancer responses to selfmedication with dichloroacetate. With informed consent, complete medical records were requested to document response to dichloroacetate, emphasizing the context of monotherapy with dichloroacetate. Of ten patients agreeing to such an evaluation, only one met the criteria of having comprehensive clinic records as well as pathology, imaging and laboratory reports, along with single agent therapy with dichloroacetate. That individual is the focus of this report. In this case report of a man with documented relapse after state-of-the-art chemotherapy for non-Hodgkin’s lymphoma, a significant response to dichloroacetate is documented with a complete remission, which remains ongoing after 4 years. Dichloroacetate appears to be a novel therapy warranting further investigation in the treatment of cancer. Background The metabolic profile of malignancy has been characterized as one associated with metabolic adaptations directed to preferentially utilize pathways involved with glycolysis (Warburg et al. 1927), which in the recent literature has been termed the glycolytic phenotype of cancer. (Bui and Thompson 2006; Fang et al. 2008; Gatenby and Gawlinski 2003) In essence, this glycolytic phenotype is a Darwinian adaptation in that the cancer cell diminishes and undermines the metabolic pathways of glucose oxidation used by normal cells for energy production, and also for tumor cell elimination (Fang et al. 2008). One crucial normal cell function compromised in the battle with cancer involves mitochondrial programmed cell death or apoptosis. On the basis of the…

Anticancer drugs that target metabolism: is dichloroacetate the new paradigm?

Ioanna Papandreou, Tereza Goliasova, and Nicholas C. Denko Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, CA Keywords: tumor metabolism, pyruvate dehydrogenase, Warburg effect, metabolic inhibitorsAbbreviations: DCA: dichloroacetate; HIF1: hypoxia-inducible factor 1; LDH: lactate dehydrogenase; PDC: pyruvate dehydrogenase complex; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PDP: pyruvate dehydrogenase phosphatase Correspondence to: Nicholas C. Denko, Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USATel.: 650-724-5066, Fax: 650-723-7382,E-mail: nicholas.denko@stanford.edu Received: 22 Jul 2010Accepted: Accepted 30 Sep 2010Online: 18 Oct 2010DOI: 10.1002/ijc.25728 In the past 20 years, the number of articles containing ‘‘tumor metabolism’’ has increased from 3 to 28 per year, and the number of times these articles have been cited has increased from 23 to 929 per year (ISI, Thompson Reuters statistics). The renewed interest in understanding the mechanisms and consequences of altered tumor metabolism has clearly captured the imagination of the scientific community. The idea that tumors have altered metabolism was first recognized by Nobel Prizewinning biochemist Otto Warburg when describing glucose metabolism.1 More recently, the concept that tumors are metabolically different has grown to encompass other characteristics, such as glutaminolysis, fatty acid oxidation and lipid biogenesis. There is clearly a different metabolic demand that drives these changes in cells that are continuously dividing when compared with terminally differentiated cells. The discovery of these alterations has raised the possibility that they may be therapeutically targeted because of their unique importance to cancer cells.2 The concept that metabolic changes are a response to unique demands within the tumor has been proposed,3 even when it is hard to quantitate those demands. There is an interplay between oncogenic changes in the tumor cell with the unique aspects of the tumor microenvironment that impact on cellular metabolism and vice versa (Fig. 1). It is therefore difficult to establish the exact metabolic demands within the tumor by studying the cells from the tumor grown ex vivo. The environmental conditions used to grow cells in culture are very different from the environmental conditions in vivo. High glucose Dulbecco’s modified Eagles media and an atmosphere of 21% oxygen is very different from the hypoxic and/or hypoglycemic conditions found in the tumor.4,5 The glucose concentration of 25 mM is approximately five times that of normal blood levels, and the oxygen tension is at least four times greater than that found in vivo. The fact that the cells are bathed in these metabolic substrates significantly alters their inherent metabolic programs.4,6 Elevated glucose concentrations favors glycolysis (the Crabtree effect7 ) while elevated oxygenation produces increased oxygen byproducts and shortens cellular lifespan.8 Glucose metabolism illustrates the interplay of these three factors in the tumor. Oncogenic transformation drives tumor cell proliferation more than vascular capacity, generating hypoxia. Hypoxia within the tumor microenvironment enhances glycolytic metabolism, largely through the activation of the hypoxiainducible factor 1 (HIF1) transcription factor.9 Increased glycolysis leads to increased production of lactate, which contributes to an acidic extracellular pH and further…

Metabolic Modulation of Glioblastoma with Dichloroacetate

E. D. Michelakis,1 * G. Sutendra,1 P. Dromparis,1 L. Webster,1 A. Haromy,1 E. Niven,2 C. Maguire,2 T.-L. Gammer,1 J. R. Mackey,3 D. Fulton,3 B. Abdulkarim,3 M. S. McMurtry,1 K. C. Petruk4 1Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. 2Department of Biomedical Engineering and Diagnostic Imaging, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. 3Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. 4Department of Neurosurgery, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. *To whom correspondence should be addressed. E-mail: em2@ualberta.ca Volume 2 Issue 31 31ra34  Submitted: 11 November 2009Accepted: 23 April 2010Published: 12 May 2010 Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133+ , nestin+ cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor–1α, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma. INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that exhibits extremely poor responses to approved therapies (1). Chemotherapy with temozolomide (TMZ) plus radiation therapy (RT), administered after debulking surgery, increases median survival from 12.1 months with RT alone to 14.6 months (1). The median time to progression of the tumor after RT and TMZ is only 6.9 months (1). In recurrent gliomas, the progression-free survival and the response to TMZ are much worse (2). GBMs are very vascular tumors with remarkable molecular and genetic heterogeneity (1). An ideal therapy should increase GBM apoptosis, overcome the molecular heterogeneity, inhibit angiogenesis, and cross the blood-brain barrier while having minimal systemic toxicity. On the basis of our recent findings in animal models (3, 4), we hypothesized that the orphan small-molecule dichloroacetate (DCA) fulfills these criteria and may be effective in the treatment of GBM in humans. DCA inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) (5). By inhibiting PDK, DCA activates pyruvate dehydrogenase…

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

Tiziana Tataranni 1 and Claudia Piccoli 1,2 1Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), 85028, Italy 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia 71121, Italy Correspondence should be addressed to Tiziana Tataranni; tiziana.tataranni@crob.it Guest Editor: Kanhaiya Singh Copyright © 2019 Tiziana Tataranni and Claudia Piccoli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 24 July 2019Revised: 12 September 2019Accepted: 11 October 2019Published online: 14 November 2019 An extensive body of literature describes anticancer property of dichloroacetate (DCA), but its effective clinical administration in cancer therapy is still limited to clinical trials. The occurrence of side effects such as neurotoxicity as well as the suspicion of DCA carcinogenicity still restricts the clinical use of DCA. However, in the last years, the number of reports supporting DCA employment against cancer increased also because of the great interest in targeting metabolism of tumour cells. Dissecting DCA mechanism of action helped to understand the bases of its selective efficacy against cancer cells. A successful coadministration of DCA with conventional chemotherapy, radiotherapy, other drugs, or natural compounds has been tested in several cancer models. New drug delivery systems and multiaction compounds containing DCA and other drugs seem to ameliorate bioavailability and appear more efficient thanks to a synergistic action of multiple agents. The spread of reports supporting the efficiency of DCA in cancer therapy has prompted additional studies that let to find other potential molecular targets of DCA. Interestingly, DCA could significantly affect cancer stem cell fraction and contribute to cancer eradication. Collectively, these findings provide a strong rationale towards novel clinical translational studies of DCA in cancer therapy. INTRODUCTION Cancer is one of the leading causes of death worldwide. Despite the significant progression in diagnostic and therapeutic approaches, its eradication still represents a challenge. Too many factors are responsible for therapy failure or relapse, so there is an urgent need to find new approaches to treat it. Apart from the typical well-known properties featuring malignant cells, including abnormal proliferation, deregulation of apoptosis, and cell cycle [1, 2], cancer cells also display a peculiar metabolic machine that offers a further promising approach for cancer therapy [3–5]. Our group had already suggested the importance of a metabolic characterization of cancer cells to predict the efficacy of a metabolic treatment [6]. Drugs able to affect cancer metabolism are already under consideration, showing encouraging results in terms of efficacy and tolerability [7]. In the last decade, the small molecule DCA, already used to treat acute and chronic lactic acidosis, inborn errors of mitochondrial metabolism, and diabetes [8], has been largely purposed as an anticancer drug. DCA is a 150 Da water-soluble acid molecule, analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms (Figure 1(a)) [9]. DCA administration in doses ranging from 50 to…

METFORMIN ENHANCES ANTITUMOR ACTION OF SODIUM DICHLOROACETATE AGAINST GLIOMA C6

D.L. Kolesnik*, O.N. Pyaskovskaya, O.V. Yurchenko, G.I. SolyanikR.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, UkraineSubmitted: May 06, 2019. *Correspondence: E-mail: denkolesnik83@gmail.com Abbreviations used: DCA — sodium dichloroacetate; MTF — metformin; Δψm — mitochondrial membrane potential; IC50 — half maximal inhibitory concentration Abstract It is known that the arsenal of chemotherapeutic agents for the treatment of malignant brain tumors is quite limited, which causes the high relevance of research aimed at finding new effective antitumor regimens, including the use of energy metabolism modifiers. Aim: To investigate the anti-glioma activity of sodium dichloroacetate (DCA) and metformin (MTF) used in combination in vitro and in vivo. Materials and Methods: Cell survival, cell cycle, apoptosis, mitochondrial membrane potential (Δψm), ATP level, the glucose consumption rate, and lactate production rate were determined in vitro in cultured glioma C6 cells. The antitumor action of agents in vivo was evaluated routinely by the prolongation of the life span of rats with transplanted intracerebral glioma C6 and was confirmed by histological examination of tumor tissue. Results: The half maximal inhibitory concentration (IC50) for DCA and MTF used separately was 79.2 ± 2.1 mM and 78.4 ± 4.0 mM, respectively, whereas IC50 for DCA used in combination with 7.8 mM MTF was 3.3 fold lower (24.0 ± 1.2 mM, p < 0.05). The 1-day incubation of cells with DCA at a concentration close to IC50 (25 mM), in combination with MTF at a concentration by order lower than IC50 (7.8 mM), in contrast to their separate use, resulted in a decrease in the number of viable cells by 40% (p < 0.05); redistribution of the cells by the cell cycle phases toward decreased proportion of cells in the S-phase by 46% (p < 0.05) and an increased percentage of cells in the G0/G1 phase by 24% (p < 0.05) compared to similar indices in the control. High proapoptotic activity of DCA in combination with MTF was supported by a significantly higher percentage of apoptotic cells in vitro than in the control (18.9 ± 4.4% vs 5.7 ± 1.3%, p < 0.05) and a high number of tumor cells with signs of apoptosis revealed during the histological examination of tumor pathomorphosis. The combined effect of DCA and MTF resulted in almost 4-fold decrease of the glucose consumption rate by glioma C6 cells (0.23 ± 0.05 μmol/106 cells/h vs 0.91 ± 0.12 μmol/106 cells/h, p<0.05) compared to the corresponding parameters in the control, and 2-fold increased rate of lactate production (1.06 ± 0.03 μmol/106 cells/h vs 0.53 ± 0.03 μmol/106 cells/h, p < 0.05). At the same time, both Δψm and the level of intracellular ATP in the glioma C6 cells treated with DCA and MTF, both separately and in combination, did not differ significantly from those indices in the control. In in vivo studies, the average life span of rats with intracranial transplanted glioma C6, treated with DCA in combination with MTF in a total dose of 1.1 and 2.6 g/kg body…

Dichloroacetate potentiates tamoxifen-induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor

Sang Hyeok Woo1,*, Sung-Keum Seo1,*, Yoonhwa Park1,2, Eun-Kyu Kim3, Min-Ki Seong4, Hyun-Ah Kim4, Jie-Young Song1, Sang-Gu Hwang1, Jin Kyung Lee5, Woo Chul Noh4, In-Chul Park1 1Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea 2School of Life Science and Biotechnology, Korea University, Seongbuk-gu, Seoul, 02841, Republic of Korea 3Department of Surgery, Breast Cancer Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, 13620, Republic of Korea 4Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea 5KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, 01812, Republic of Korea *These authors contributed equally to this work Correspondence to: In-Chul Park, email: parkic@kcch.re.kr Keywords: tamoxifen, breast cancer, dichloroacetate, epidermal growth factor receptor, pyruvate dehydrogenase kinase  Received: May 18, 2016 Accepted: July 22, 2016 Published online: August 01, 2016 Abstract Metabolic reprogramming in cancer cells has recently been recognized as an essential hallmark of neoplasia. In this context, metabolic alterations represent an attractive therapeutic target, and encouraging results with drugs targeting various metabolic processes have been obtained in preclinical studies. Recently, several studies have suggested that dichloroacetate (DCA), a specific pyruvate dehydrogenase kinase inhibitor, may be a potential anticancer drug in a large number of diverse tumors. However, the precise mechanism is not fully understood, which is important for the use of DCA in cancer treatment. In the present study, we found that DCA sensitized MCF7 breast cancer cells to tamoxifen-induced cell death by decreasing epidermal growth factor receptor (EGFR) expression. The downregulation of EGFR was caused by degradation of the protein. Furthermore, p38 mitogen-activated protein kinase played an important role in DCA/tamoxifen-induced EGFR degradation. Finally, DCA also promoted comparable tamoxifen-induced cell death in tamoxifen-resistant MCF7 cells, which were established by long-term treatment with tamoxifen. In summary, our results suggest that DCA is an attractive potential drug that sensitizes cells to tamoxifen-induced cell death and overcome tamoxifen resistance via downregulation of EGFR expression in breast cancer cells. INTRODUCTION Proliferating cancer cells have considerably different metabolic requirements compared to most normal differentiated cells. For example, to support rapid cell growth and proliferation, cancer cells differentially alter metabolic flux compared to the surrounding tissue to provide sufficient bioenergetics and biosynthetic intermediates. A well-known phenomenon observed in most cancer cells is a shift to aerobic glycolysis, regardless of oxygen supply, which is termed the “Warburg effect”, in which pyruvate is directly converted to lactic acid instead of entering the citric acid cycle [1]. As all cancer cells are dependent on this change in metabolism, these altered pathways represent attractive therapeutic targets [2]. Efforts have been made to target reprogrammed metabolism alone or in combination with cancer chemotherapy both in preclinical and clinical studies [3]. Interestingly, this cancer-specific metabolic remodeling is reversed by dichloroacetate (DCA), a mitochondria-targeting small molecule that can penetrate most tissues after oral administration [4]. It specifically inhibits pyruvate dehydrogenase kinase (PDK), a member of the kinase family, leading to reactivation…

Medullary thyroid carcinoma relapse reversed with dichloroacetate: A case report

Dana Flavin Foundation for Collaborative Medicine and Research, Greenwich, CT, USA and AMC/co Klinik im Alpenpark, Ringsee, Germany Correspondence to: Dr Dana Flavin, Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT, USA E-mail: dana@collmed.com Received: April 7, 2010Accepted: June 15, 2010DOI: 10.3892/ol_00000158 Abstract A 51-year-old male patient diagnosed with medullary thyroid carcinoma (MTC) in 2001, with progression to lung metastases following adriamycin therapy, was then successfully treated with dimethyltriazenoimidazole carboximide. He remained in partial remission for 7 years following numerous chemotherapy attempts to induce partial remission. In October 2008, the patient, then 58 years old, relapsed with numerous tumors throughout his central body. On December 1, 2008, the tumor marker for MTC, calcitonin, was at 38,611 pg/ ml, i.e., much higher than the norm of <20 pg/ml. Since all other chemotherapy attempts had failed, he was ineligible for any new studies. Subsequently, the patient was immediately started on 10 mg/kg of dichloroacetate (DCA). By April 2009, the calcitonin level was reduced to 2,000 pg/ml. In May 2009, a new positron emission tomography showed a dramatic reduction in all tumor locations. The patient presently remains in remission and continues receiving the same dosage of DCA, with his tumor marker remaining stable in laboratory data since November 2009. Key words: dichloroacetate, medullary thyroid carcinoma INTRODUCTION Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumor arising from neural crest-derived parafollicular C cells (calcitonin-producing cells) of the thyroid gland (1), a component of multiple endocrine neoplasia type 2 or MEN2 syndromes (2), accounting for approximately 4% of all thyroid cancers. Although 25-30% of MTC cases are inherited disorders, the remaining cases consist of sporadic forms of the disease (3). The 3-year survival rate of patients with differentiated thyroid cancer and radioactive iodine resistance is less than 50%, with little response obtained from standard cytotoxic chemotherapies (4). In endocrine malignancies, such as thyroid carcinoma, the treatment of choice is surgery; however, this approach is only successful in early stage disease. MTC is an incurable disease once metastases become unresectable (5). Treatment options for advanced endocrine malignancies remain unsatisfactory and are associated with poor patient prognoses. Cytotoxic chemotherapy and radiation therapy, which are associated with significant toxicity, often show only limited and transient efficacy (6). Tyrosine kinase inhibitors particularly effecting the RET (rearranged during transfection) proto-oncogene gain of function activity, such as with vandetanib, sorafenib and sunitinib, appear to be promising. However, the low rate of partial responses and the absence of complete responses in all of the various trials of monotherapy emphasize the need for novel and more effective single or combination of agents with acceptable toxicity (3). Case report This study presents a male MTC patient with lung metastases, who developed new tumors seven years after surgical intervention and successful chemotherapy with dimethyltriazenoimidazole carboximide (DTIC) and 5-fluorouracil. Initially diagnosed in 2001, the 51-year-old patient with MTC and lymph node involvement had a sporadic form of the disease, while his twin brother, who was also negative for any genetic factor, was disease-free.…

A Novel Form of Dichloroacetate Therapy for Patients With Advanced Cancer: A Report of 3 Cases

Akbar Khan, MD; Denis Marier, ND; Eric Marsden, ND; Douglas Andrews, ND; Isaac Eliaz, MD Akbar Khan, MD, is the medical director of Medicor Cancer Centres, Inc, in Toronto, Ontario, Canada. Denis Marier, ND, is the director of Canadian Clinic for Integrative Medicine in Windsor, Ontario. Eric Marsden, ND, is the director of Marsden Center of Naturopathic Excellence in Maple, Ontario. Douglas Andrews, ND, is a staff naturopathic doctor at Medicor Cancer Centres, Inc. Isaac Eliaz, MD, is the director of Amitabha Medical Clinic, in Santa Rosa, California. Corresponding author: Akbar Khan, MD E-mail address: akhan@medicorcancer.com Abstract Oral dichloroacetate sodium (DCA) is currently under investigation as a single agent and as an adjuvant for treatment of various cancers. One of the factors limiting its clinical use in a continuous oral regimen is a doserelated, reversible neurotoxicity, including peripheral neuropathy and encephalopathy. The intravenous (IV) route has a number of potential advantages, including (1) pulsed dosing to achieve higher concentrations than feasible with oral use, (2) a longer washout period to reduce the potential for neurotoxicity, and (3) a bypassing of the digestive system, which is particularly significant for advanced-stage cancer patients. Data were available on high-dose IV DCA (up to 100 mg/kg/dose) that have confirmed its safety, both in healthy volunteers and in critically ill patients, allowing the authors to begin offlabel treatment of cancer patients. In several of their patients treated with IV DCA, the authors observed clinical, hematological, or radiological responses. This article presents 3 cases with patients who had recurrent cancers and for whom all conventional therapies had failed: (1) a 79-y-old male patient with colon cancer who had liver metastases, (2) a 43-y-old male patient with angiosarcoma who had pancreatic and bone metastases, and (3) a 10-y-old male patient with pancreatic neuroendocrine carcinoma who had liver metastases. (Altern Ther Health Med. 2014;20(suppl 2):21-28.) Oral sodium dichloroacetate (DCA) is a drug that is currently under investigation as a single agent and an adjunctive cancer treatment.1 As of this writing, an ongoing phase I trial of oral DCA for recurrent or metastatic solid tumors is occurring at the University of Alberta and 2 trials of oral DCA for head and neck cancers are occurring at Stanford University. DCA has been extensively studied by Stacpoole2-5 for the treatment of congenital lactic acidosis, which includes a group of inherited mitochondrial diseases. The safety profile for use of oral DCA in humans has been established through this body of work. The drug has been found to be relatively safe, with no hematologic, cardiac, pulmonary, or renal toxicity.6 The main toxicity is neurological, primarily peripheral neuropathy, and this condition is reversible.7 DCA-induced delirium has been observed and is rapidly reversible upon discontinuation of the drug.8 An asymptomatic but reversible elevation of liver enzymes can occur in a small percentage of patients.9 In January 2007, Bonnet et al10 published a groundbreaking paper that demonstrated that DCA was effective in treating human breast, lung, and brain cancers in vitro and in vivo (in…

Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis

Walter Lemmoa, c, Gerard Tanb Manuscript accepted for publication March 04, 2016 a LEMMO Integrated Cancer Care Inc., 327 Renfrew Street, Vancouver, BC V5K 5G5, CanadabGerard Tan & Associates Integrative Cancer Centre, Suite 105-2295 West Broadway, Vancouver, BC V6K 2E4, Canadac Corresponding Author: Walter Lemmo, ND, FABNO, LEMMO Integrated Cancer Care Inc., 327 Renfrew Street, Vancouver, BC V5K 5G5, Canada. Email: walter@lemmo.comdoi: http://dx.doi.org/10.14740/jmc2456w Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.orgThis is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited Abstract Here we present an observational case report of a 49-year-old female, non-smoker, having a poor performance status with non-small-cell lung cancer and leptomeningeal carcinomatosis (LMC), who upon introduction of oral dichloroacetate (DCA) survived approximately 64 weeks (454 days) following palliative whole brain radiation without the need for chemotherapy or further targeted therapy to specifically address the LMC. To our knowledge, this is the first case report incorporating the use of DCA in LMC. Our findings are discussed in the context of previously reported applications of DCA in malignancies of the central nervous system. Key words: Dichloroacetate; Dichloroacetic acid; Non-small-cell lung cancer; Leptomeningeal carcinomatosis INTRODUCTION Leptomeningeal carcinomatosis (LMC) can be a challenging comorbidity of various malignancies, in particular breast and lung cancer [1, 2]. Common treatment protocols favor chemotherapeutic approaches, including intrathecal (IT) applications [3, 4], targeted agents [5], palliative radiation [6, 7], and the use of a ventriculoperitoneal (VP) shunt to alleviate hydrocephalus complications [8-10]. There is a great need for research into new treatment modalities that are convenient, low risk, and efficacious, as the median survival continues to be only a few months for patients with advanced non-small-cell lung cancer (NSCLC). Case Report A 49-year-old non-smoker woman presented in May 2006 with inoperable NSCLC IIIb diffusely involving the right lung along with a right pleural effusion. Three cycles of gemcitabine and cisplatin beginning on July 26, 2006 were deemed ineffective. On September 18, 2006, she responded to talc pleurodesis. Subsequently, on October 5, second line paclitaxel was initiated but due to significant toxicity, it was replaced by nab-paclitaxel on October 26; the fourth and final doses were on January 2, 2007 due to progressive disease. She was then switched to erlotinib 100 mg/day on January 23, 2007, which continued until February 2009. Epidermal growth factor receptor (EGFR) mutational status was unknown as, at the time, this test was not subsidized by the Medical Service Plan of British Columbia, Canada. Despite stable appearing chest X-ray imaging between February 27, 2007 and December 29, 2007, and computerized tomography (CT) chest and abdomen imaging revealing no further abnormal findings as of April 28, 2008, carcinoembryonic antigen (CEA) continued to gradually rise beginning June 28, 2007 with a value of 28, to 170 on April 28, 2008. The CEA rise, in this case, appeared to correlate with…

Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate

Akbar Khan Medical Director, Medicor Cancer Centres Inc., Toronto, Canada Abstract Renal squamous cell carcinoma is a rare form of renal cancer which is considered incurable once metastases develop. Prognosis is poor and average survival of advanced stage disease is typically in the range of several months, despite all available conventional therapies. We describe the case of a 72 year old female with metastatic renal squamous cell carcinoma who had a radical nephrectomy with positive surgical margins, renal vein invasion and metastases to multiple abdominal lymph nodes. She received a course of palliative radiotherapy to the abdomen with 4500cGy in 25 fractions over 5 weeks. Following radiotherapy, she was treated with a cyclic regimen of oral sodium dichloroacetate (“DCA”). Treatment was discontinued after 3 months due to development of peripheral neuropathy. Follow-up imaging upon completion of DCA treatment revealed no sign of metastatic disease. The neuropathy gradually improved and computed tomography imaging four years later demonstrated no cancer recurrence. The patient continues to feel well with no clinical evidence of recurrence five years after completion of therapy, and is living a normal and active life. Key words: Dichloroacetate, radiotherapy, renal squamous cell carcinoma, remission Copyright © 2012 Akbar Khan. This is an open access article distributed under the Creative Commons Attribution License unported 3.0, which permits unrestricted use, distribution, and reproduction in any medium, provided that original work is properly cited. Contact author: Akbar Khan E-mail: akhan@medicorcancer.com INTRODUCTION Renal squamous cell carcinoma (“RSCC”) is a rare form of renal cancer which originates from the renal pelvis. RSCC comprises about 0.5 - 0.8% of all malignant renal tumours (Bhaijee 2012). Although surgery is sometimes curative for localized disease, metastatic renal squamous cell carcinoma (“mRSCC”) is considered incurable (Holmang et al. 2007). Multiple publications from physicians with experience treating RSCC have established that this cancer type is radio-resistant, and that systemic chemotherapy provides little benefit. (Bhandari et al. 2010), (Di Battista et al. 2012), (Kimura et al. 2000), (Li and Cheung 1987). Average survival of advanced stage disease is extremely poor (in the range of several months) and five year survival is reported to be less than 10% (Holmang et al. 2007). In a review of 15 cases, Lee et al. reported a median survival of 3.5 months (Lee et al. 1998). A Medline search was conducted (Medline RSCC 2012) to determine if any cases of long-term complete remission of mRSCC had been recorded. This revealed over 200 citations of RSCC but only one published case of 5 year complete remission/cure (Carlson 1960). In this case, the patient had complete nephro-ureterectomy, including resection of peri-renal fat and a cuff of bladder. Pathology did not demonstrate any involvement of surgical margins and there were no metastases reported. Sodium dichloroacetate (“DCA”) is a drug that has been extensively studied for the treatment of congenital lactic acidosis which is comprised of a group of inherited mitochondrial diseases (Stacpoole et al. 2006), (Stacpoole et al. 1992), (Stacpoole et al. 1988). The safety profile of DCA…

Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells

Ramon C Sun1,2, Philip G Board1 and Anneke C Blackburn1* 1 Molecular Genetics Group, Department of Translational Biosciences, John Curtin School of Medical Research, Building 131, Australian National University, P.O. Box 334, Canberra ACT 0200, AUSTRALIA 2 Department of Radiation Oncology, Stanford School of Medicine, Stanford CA 94305 USA.1*Correspondence: Anneke.Blackburn@anu.edu.au© 2011 Sun et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Received: 3 May 2011 Accepted: 18 November 2011Published: 18 November 2011 Abstract BackgroundCancer cells have a different metabolic profile compared to normal cells. The Warburg effect (increased aerobic glycolysis) and glutaminolysis (increased mitochondrial activity from glutamine catabolism) are well known hallmarks of cancer and are accompanied by increased lactate production, hyperpolarized mitochondrial membrane and increased production of reactive oxygen species. MethodsIn this study we target the Warburg effect with dichloroacetate (DCA) and the increased mitochondrial activity of glutaminolysis with arsenic trioxide (ATO) in breast cancer cells, measuring cell proliferation, cell death and mitochondrial characteristics. ResultsThe combination of DCA and ATO was more effective at inhibiting cell proliferation and inducing cell death than either drug alone. We examined the effect of these treatments on mitochondrial membrane potential, reactive oxygen species production and ATP levels and have identified new molecular mechanisms within the mitochondria for both ATO and DCA: ATO reduces mitochondrial function through the inhibition of cytochrome C oxidase (complex IV of the electron transport chain) while DCA up-regulates ATP synthase b subunit expression. The potentiation of ATO cytotoxicity by DCA is correlated with strong suppression of the expression of c-Myc and HIF-1a, and decreased expression of the survival protein Bcl-2. ConclusionThis study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential. KeywordsDichloroacetate, breast cancer, electron transport chain, mitochondria, arsenic trioxide Introduction Arsenic trioxide (ATO) has been used as a therapeutic agent for over 2000 years. Originating from China [1], it is currently being used against acute promyeloid leukemia (APL) in patients who have relapsed following alltrans-retinoic acid/anthracycline therapy and is being promoted for first line therapy of de novo APL [2-4]. ATO is known as a hyper-reactive molecule and could potentially bind to thiol groups in many proteins [2,5]. Its ability to bind to the thiol-rich, mutant protein PML-RAR-α produced from a chromosome translocation in APL has made it an effective drug in APL [2,5,6]. ATO has been shown to induce apoptosis in a variety of cancer cell lines in vitro and in vivo [7,8], but it has been difficult to consider ATO for clinical use in tumor types other than APL due to the lack of knowledge of the molecular targets that result in its cytotoxicity. In the past 10 years, physiological changes within cancer cells in response to ATO treatment have been well characterized, and many clinical trials for new applications of ATO are…

Non-Hodgkin’s Lymphoma Reversal with Dichloroacetate

Dana F. Flavin1, 2 1Klinik im Alpenpark, Defreggerweg 2-6, Ringsee, 83707 Tegernsee, Germany2 Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT 06830, USA Correspondence should be addressed to Dana F. Flavin, dana@collmed.comReceived: 4 June 2010Accepted: 23 July 2010Academic Editor: Michael A. CarducciCopyright © 2010 Dana F. Flavin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In June 2007, a 48-year-old male patient, diagnosed with Stage 4 Non-Hodgkin’s Follicular Lymphoma (NHL), was treated for 3 months with conventional chemotherapy resulting in a complete remission. Almost one year later tumors returned in the nasopharynx and neck lymph glands. Refusing all suggested chemotherapies, the patient began self-administering dichloroacetate (DCA) 900 mg daily with a PET scan showing complete remission four months later. Since his last PET scan, May, 2009, he remains tumor-free from continuous DCA usage. INTRODUCTION Non-Hodgkin’s lymphoma (NHL), a cancer of the lymph system that can start anywhere in body, affects 400,000+ people in the United States with 66,000 new cases in 2009 [1]. NHL often presents as a low grade fever with sweating, swollen lymph nodes, general malaise, and fatigue. Although it responds well to established therapies, including chemotherapy and radiation [2], more aggressive newer treatments are being developed, including chemotherapy with whole body radiation followed by stem cell transplants [3]. While these treatments have resulted in complete remission in some patients [4], other patients, aware of the quality of life compromises sustained with aggressive therapies [3], seek alternate avenues of treatment with professionals or on their own, many of which are nonconventional or in experimental stages. One such therapy is dichloroacetate (DCA) [5]. DCA is a by-product of water chlorination [6, 7] that inhibits aerobic glycolysis. It has been used in medicine for over 30 years [8] as an investigational drug to treat severe metabolic disorders such as diabetes and hypercholesterolemia [5, 9] as well as the treatment of congenital lactic acidosis in North American children [10]. The bioavailability [11] and pharmacokinetics [12] of DCA have been well researched over several decades in adults [6], children [13, 14], and animals [15]. As a medicinal, DCA is generally well tolerated from dosages between 10 mg/Kg and 50 mg/Kg, although prolonged exposure is associated with peripheral neuropathy [16]. Its activation of the pyruvate dehydrogenase enzyme (PDH) of the mitochondria decreases glycolysis and reactivates glucose oxidation, a favorable approach to ameliorate lactic acidosis [9]. Cancer cells predominantly utilize a system of glycolysis for energy instead of the glucose oxidation used by healthy cells. Cancer appears to be a form of intracellular lactic acidosis caused by a block in the oxidation of glucose at the level of PDH (pyruvate dehydrogenase). The glycolysis metabolism of glucose increases cancer cells’ lactic acid and reduces the intracellular pH [7] resulting major shifts in the intracellular biochemistry. Aerobic glycolysis, known as the “Warburg Effect” [17], inactivates mitochondrial respiration which allows cancer…

Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells

Serena Vella1*, Matteo Conti2*, Roberta Tasso1, Ranieri Cancedda1,3 and Aldo Pagano1,3 1 Oncology, Biology, and Genetics Department (DOBiG), University of Genoa, Genoa-Italy2 Laboratory of Clinical Pharmacology and Toxicology, Ospedale S. Maria delle Croci, 48100 Ravenna-Italy3 National Institute for Cancer Research (IST) Genoa, Largo R. Benzi, 10, 16132 Genoa-Italy The small, water soluble molecule Dichloroacetate (DCA) is recently arousing lively interests in the field of cancer therapy for it has been shown to be able to inhibit the growth of human tumors acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells. Neuroblastoma was one of the tumor types on which DCA was considered ineffective as it is composed of cells with few recognized mitochondrial anomalies. Neuroblastoma, however, is composed of different cell types in terms of metabolism, phenotype and malignant potential. Despite the above prediction, in this work, we show that (i) DCA exhibits an unexpected anticancer effect on NB tumor cells and (ii) this effect is selectively directed to very malignant NB cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. This result supports the need of a detailed investigation of DCA anticancer properties against this tumor type with the final aim of its possible use as therapeutic agent. The small molecule/orphan drug DCA recently stepped into the limelight for its capacity to restrict glioblastoma multiforme (GBM) tumor growth at dosages compatible with no side effects.1–4 Thus, considering its well-tolerated toxicity together with its low cost, DCA is arousing lively interest for its potential use in cancer therapy and in the cure of certain tumor types.5 Indeed, although DCA has been shown to be effective in small cell lung carcinoma,6 breast,7 prostate8 and endometrial9 cancers and glioblastoma cell lines,2 the efficacy of this small molecule as anticancer treatment has been so far clinically demonstrated only in human GBM so that the proved efficacy of DCA on other malignancies still remains to be evaluated.10 In detail, due to its mechanism of action, DCA is expected to be ineffective on those tumors characterized by a low mitochondrial polarization such as oat cell lung cancer, lymphomas, neuroblastoma (NB) and sarcomas.5 DCA as an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) activates pyruvate dehydrogenase (PDH), a gatekeeper enzyme that regulates the flux of pyruvate into the mitochondria, increasing the ratio of glucose oxidation to glycolysis.4–6 Bonnet et al. showed that this oxidative phosphorylation boosting is selectively pro-apoptotic in cancer cells, leading to a decrease in their typical mitochondrial hyperpolarization associated with apoptosis resistance.6 Despite NB being initially considered one tumor type on which DCA is most likely ineffective, due to its specific small cell feature and presumed absence of mitochondrial membrane hyperpolarization,5 proliferating NB cells are sustained by a glycolytic phenotype.11 We studied the possible efficacy of DCA treatment in inhibiting the growth of human NB nodules generated in NOD-SCID mice. Surprisingly, we observed that DCA significantly restricts in vivo tumor growth. In human NB tumors, there are three distinct cell…

Long-term stabilization of metastatic melanoma with sodium dichloroacetate

Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn Akbar Khan, Douglas Andrews, Medicor Cancer Centres Inc., Toronto, ON M2N 6N4, Canada Jill Shainhouse, Insight Naturopathic Clinic, Toronto, ON M4P 1N9, Canada Anneke C Blackburn, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia  Author contributions: Khan A treated the patient and wrote most of the case report; Andrews D assisted in development of the natural medication protocol for reduction of DCA side effects, and wrote a portion of the case report; Shainhouse J treated the patient with natural therapy; Blackburn AC interpreted the case report in the context of the literature on in vitro and in vivo DCA research, wrote parts of the introduction and discussion, and reviewed the manuscript overall. Informed consent statement: The patient described in this manuscript has given consent to publish her case anonymously.  Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc., 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada. akhan@medicorcancer.comTelephone: +1-416-2270037Fax: +1-416-2271915   Received: January 30, 2017  Peer-review started: February 12, 2017  First decision: March 28, 2017  Revised: May 5, 2017  Accepted: May 30, 2017  Article in press: May 31, 2017  Published online: August 10, 2017 Abstract Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years’ duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain longterm stability in patients with advanced melanoma. Key words: Dichloroacetate; Cancer; BRAF; Melanoma; Cytostatic © The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007. It has been shown that…

Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy (Case report)

Akbar Khan, Doug Andrews, Anneke C Blackburn Akbar Khan, Douglas Andrews, Medicor Cancer Centres Inc., Toronto, ON M2N 6N4, Canada Anneke C Blackburn, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia  Author contributions: Khan A treated the patient and wrote most of the case report; Andrews D treated the patient, designed the natural therapy protocols, and co-wrote the case report; Blackburn AC performed in vitro and in vivo work demonstrating DCA’s effects as a cytostatic agent, and wrote the parts of the case report dealing with the in vitro and in vivo DCA research. Institutional review board statement: Not applicable.  Informed consent statement: The patient described in this manuscript has given consent to publish her case anonymously.  Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc., 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada. akhan@medicorcancer.comTelephone: +1-416-2270037Fax: +1-416-2271915  Received: April 30, 2016  Peer-review started: May 3, 2016  First decision: June 17, 2016  Revised: July 23, 2016  Accepted: August 6, 2016  Article in press: August 8, 2016  Published online: October 16, 2016 Abstract Oral dichloroacetate sodium (DCA) has been investi-gated as a novel metabolic therapy for various cancers since 2007, based on data from Bonnet et al that DCA can trigger apoptosis of human lung, breast and brain cancer cells. Response to therapy in human studies is measured by standard response evaluation criteria for solid tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging.However, Blackburn et al have demonstrated that DCA can also act as a cytostatic agent in vitro and in vivo , without causing apoptosis (programmed cell death). A case is presented in which oral DCA therapy resulted in tum our stabilization of stage 4 colon cancer in a 57 years old female for a period of nearly 4 years, with no serious toxicity. Since the natural history of stage 4 colon cancer consists of steady progression leading to disability and death, this case highlights a novel use of DCA as a cytostatic agent with a potential to maintain long-term stability of advanced-stage cancer. Key words: Dichloroacetate; Cancer; Colon; Colorectal; Cytostatic; Stabilization; Growth inhibition; Intravenous © The Author(s) 2016. Published by Baishideng Publishing  Group Inc. All rights reserved. Core tip: Oral dichloroacetate sodium (DCA) has been investigated as a novel metabolic therapy for various cancers. Response to therapy in human studies is measured by standard…

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