Through metabolomic profiling using a combination of highthroughput liquid and gas chromatographybased mass spectrometry on a total of 69 patientderived glioma specimens, this report documents the discovery of a parallel. Sodium dichloroacetate dca, cas 2156561 agcr684, is a synthetic high purity chemical. Jan 05, 2019 dichloroacetate dca is a synthetic halogenated organic acid which has been used in rare diseases like congenital lactic acidosis. To date, this is the first study investigating dca for endometriosis pain and assessing whether it is possible to achieve acceptable recruitment and retention rates. It is defined by the presence of endometriumlike tissue lesions outside the uterus, most commonly on the pelvic peritoneum. Bioenergetic modulation with dichloroacetate reduces the. Hamlet human alphalactalbumin made lethal to tumor cells is a molecular complex derived from human breast milk that kills tumor cells by a process resembling programmed cell death. Medline is the largest medical database in the world, and contains information on published dca research. Furthermore, fresh experimental evidence with pi3k antagonists in melanoma, glioblastoma, and prostate cancer shows that mitochondrial metabolism drives an elaborate process of tumor adaptation. Metabolictargeted combination therapy with dichloroacetate and. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma. Oct 18, 2010 a number of metabolic pathways that seem to be important for tumor growth are being touted as novel targets for anticancer drug development.
Research article cancer metabolic modulation of glioblastoma. May 12, 2010 we tested whether the smallmolecule and orphan drug dichloroacetate dca can reverse this cancerspecific metabolic and mitochondrial remodeling in glioblastoma. Metabolic modulation of epigenetics in gliomas was previously summarized. However, in the last years, the number of reports supporting dca. Ros modulate cellular function and integrity through oxidation of macro. All endometriosis drug approvals to date have been contraceptive, limiting their use in women of childbearing age. In addition to the clinical and neuropathology reports, we confirmed gbm identity with fig. It confirmed that dca is an effective anticancer drug for treating glioblastoma patients metabolic modulation of glioblastoma with dichloroacetate, science translational medicine, vol 2, issue 31. In addition, a recent study has tested the efficacy of dichloroacetate in a small cohort of patients with glioblastoma, suggesting metabolic modulation through pdk inhibition as a novel therapeutic strategy for the treatment of this devastating brain tumor.
Research article cancer metabolic modulation of glioblastoma with dichloroacetate e. Unlike normal cells that obtain 95% of their energy requirements via oxidative respiration, cancer cells rely heavily on glucose in a process known as anaerobic glycolysis 1. Metabolic modulation pyruvate dehydrogenase kinase warburg effect dichloroacetate abstract background. Based on these recent findings, we hypothesized that the two metabolic modulators dca and met could. Metabolic modulation of glioblastoma with dichloroacetate mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate lactate inhibits lipolysis in fat cells through activation of an orphan gproteincoupled receptor, gpr81. Complex i inhibition augments dichloroacetate cytotoxicity through. Potential glioblastoma cancer cure with the help of dca dca. The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Dichloroacetic acid dca, sometimes called bichloroacetic acid bca, is the chemical compound with formula c h cl 2 cooh.
Through this line of investigation, we identified the metabolic intermediate of cystine catabolism cysteine sulfinic acid csa as a novel metabolite associated with glioblastoma. Pyruvate dehydrogenase kinases pdks have recently emerged as an attractive target for cancer therapy. Controlled clinical trial of dichloroacetate for treatment. Metabolic modulation of glioblastoma with dichloroacetate findings on the use of dca in brain tumours. Glioblastoma multiforme gbm develops on glial cells and is the most common, as well as the deadliest, form of brain cancer 1. Glioblastoma multiforme gbm is a complicated pathological process with dysregulated methylation and histone modifications. Jan 30, 20 michelakis ed, sutendra g, dromparis p, webster l, haromy a, niven e, maguire c, gammer tl, mackey jr, fulton d et al 2010 metabolic modulation of glioblastoma with dichloroacetate. Potential glioblastoma cancer cure with the help of dca. 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. Effects of dichloroacetate as single agent or in combination with. Metformin enhances antitumor action of sodium dichloroacetate. As in pancreatic cancers, distinct combinations of genetic alterations in gbm subtypes induce a multiplicity of metabolic phenotypes, which explains the variability of gb. Metabolic modulation of glioblastoma with dichloroacetate pubmed.
We tested whether the smallmolecule and orphan drug dichloroacetate dca can reverse this cancerspecific metabolic and mitochondrial remodeling in glioblastoma. This study also observed that apoptosis was further increased in the glioblastoma stem. The robust glycolytic metabolism of glioblastoma multiforme gbm has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate dca. Smallmolecule inhibitors of the phosphoinositide 3kinase pi3k, akt, and mtor pathway currently in the clinic produce a paradoxical reactivation of the pathway they are intended to suppress. Mar 12, 2021 dichloroacetate dca may be a potential novel nonhormonal treatment for endometriosisassociated pain in women. Jan 05, 2017 the small study proved that dca could be an essential missing part of the gbm treatment.
Anticancer drugs that target metabolism wiley online library. Dec 17, 2019 endometriosis is a chronic pain condition affecting. We sought to elucidate the role of metformins reported. Pdf solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells.
Dichloroacetate as a possible treatment for endometriosis. Pyruvate dehydrogenase kinase as a potential therapeutic target. Metabolic response of glioma to dichloroacetate measured. Michelakis ed, sutendra g, dromparis p et al 2010 metabolic modulation of glioblastoma with dichloroacetate. As in pancreatic cancers, distinct combinations of genetic alterations in gbm subtypes induce a multiplicity of metabolic phenotypes, which explains the variability of gbm sensitivity to current therapies targeting its reprogrammed metabolism. Pdf repurposing dichloroacetate for the treatment of women. Dichloroacetate in simple terms, dca shifts the balance of pyruvate metabolism towards energy atp production in the mitochondria and away from conversion into lactate outside the mitochondria.
Antitumor activity of dichloroacetate on c6 glioma cell. Anticancer drugs that target metabolism, is dichloroacetate the new. Metabolic modulation of clearcell renal cell carcinoma. Metabolic response of glioma to dichloroacetate measured in. Aug 01, 2019 epigenetic and metabolic alterations incancer cells are highly associated. Pdf severe encephalopathy and polyneuropathy induced by. No controlled clinical trials of dca are available. Glioblastoma multiforme is one of the most aggressive cancers, with less than half of patients surviving beyond 1. Pdf metabolic modulation of glioblastoma with dichloroacetate. Dichloroacetate induced intracellular acidification in. The salts and esters of dichloroacetic acid are called. These investigations identified unique metabolic subtypes in glioma, with the metabolic signature of glioblastoma being consistent with anabolic metabolism. Openlabel studies indicate that oral dichloroacetate dca may be effective in treating patients with congenital lactic acidosis. If youre interested in the study, please read more below.
Pdf repurposing dichloroacetate for the treatment of. Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a. Running title evaluating dichloroacetates anticancer activity. Dichloroacetate induced intracellular acidification in glioblastoma. Sensitization of glioblastoma cells to irradiation by. Introduction glioblastoma multiforme gbm is an aggressive primary brain tumor that exhibits extremely poor responses to approved therapies 1. A 52yearold male patient was treated with standard radiochemotherapy with temozolomide for glioblastoma multiforme gbm. Data were analyzed for each patient from the time they began treatment through. For the first time, we have successfully developed dca derived inhibitors that preferentially bind to the adenosine triphosphate atp pocket of pdk isoform 1 pdk1. Jan 01, 2017 metabolic modulation of glioblastoma with dichloroacetate 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. Development of a dichloroacetic acidhemoglobin conjugate as a potential targeted anticancer therapeutic a study showing promise of a dcahb conjugate against monocytic leukemia. The potential efficacy of dca in cancer therapy comes from metabolic properties of. Recent reports demonstrate that the antidiabetic drug metformin enhances the damaging oxidative stress associated with dca treatment in cancer cells. The purpose of this research was to report results on longterm administration of dichloroacetate in 36 children with congenital lactic acidosis who participated previously in a controlled trial of this drug.
It is based on the realization that cancers unique metabolism known since warburgs report in 1923 with suppression of mitochondrial glucose oxidation and upregulation of. Repurposing dichloroacetate for the treatment of women with. Pinkd, katia carminesimmend, ronald moorea, john d lewisd. Ros modulate cellular function and integrity through oxidation of macromolecular structures. Epigenetic modulation of metabolism in glioblastoma. Dichloroacetate radiosensitizes hypoxic breast cancer cells mdpi. Kidney cancer metabolic modulation of clearcell renal cell carcinoma with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase adam kinnairda,b, peter dromparisb, bruno salemeb, vikram gurtub, kristalee watsonc, roxane paulinb, sotirios zervopoulosb, trevor stensonb, gopinath sutendrab, desmond b. More precisely, dca inhibits the activity of pyruvate dehydrogenase kinases pdks, allowing increased activity of pyruvate dehydrogenase, and the further metabolism of pyruvate within the cell mitochondria. The robust glycolytic metabolism of glioblastoma multiforme gbm has proven. Metabolic modulation of clearcell renal cell carcinoma with.
Freshly isolated glioblastomas from49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by dca. Glioblastoma multiforme gbm is an aggressive primary brain tumor that affects a huge. It has been tested in humans with skin papillomas and bladder cancer dichloroacetate treatment. Clearcell renal cell carcinoma ccrcc exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. Metabolic abnormalities in glioblastoma and metabolic. Treatment of endo hpmcs with dca normalized their metabolic phenotype and increased pdh activity, in the presence. Jan 14, 2015 metabolic oncology is an exciting new field in cancer research, offering a new window to cancers molecular plasticity and promise for the development of effective, cancerselective therapies and novel biomarkers. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma bearing mice. Like the other chloroacetic acids, it has various practical applications. Mitochondrial pyruvate dehydrogenase kinase pdk inhibitor, consequently activating pyruvate dehydrogenase pdh.
Herein, we prepared a series of compounds derived from dichloroacetate dca which inhibited cancer cells proliferation. Dichloroacetate reverses the hypoxic adaptation to. After worsening of his clinical condition, further tumorspecific treatment was unlikely to be successful, and the patient seeked help from an alternative practitioner, who administered a combination of dichloroacetate dca and artesunate art. We conducted a randomized control trial, followed by an openlabel study. Hopefully, more and more studies will be directed towards this alternative view of dealing with glioblastoma. Dec 19, 2019 dichloroacetate sodium dca is an inexpensive and simple chemical compound similar to combining vinegar and salt.
Dromparis p, webster l, haromy a, niven e, maguire metabolic modulation of. Apr 01, 2016 metabolic modulation of clearcell renal cell carcinoma with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase author links open overlay panel adam kinnaird a b peter dromparis b bruno saleme b vikram gurtu b kristalee watson c roxane paulin b sotirios zervopoulos b trevor stenson b gopinath sutendra b desmond b. Cancer metabolic modulation of glioblastoma with dichloroacetate e. The effectiveness of dichloroacetate on human glioblastoma. Metabolic modulation may be a viable therapeutic approach in the treatment of. Volume 2 issue 31 31ra34 solid tumors, including the. 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. Evaluation of longterm treatment of children with congenital. Oct 21, 2019 it confirmed that dca is an effective anticancer drug for treating glioblastoma patients metabolic modulation of glioblastoma with dichloroacetate, science translational medicine, vol 2, issue 31. Controlled clinical trial of dichloroacetate for treatment of.
Introduction glioblastoma is the most malignant form of primary brain tumor in adults. The occurrence of side effects such as neurotoxicity as well as the suspicion of dca carcinogenicity still restricts the clinical use of dca. Br j peripheral neurotoxicity was found to be due to an age cancer 99. Keywords glioblastoma, dichloroacetate, magnesium, sodium, pcna, ezh2. Dca dichloroacetate sodium treatment for cancer cancer. More recently in the era of targeted therapy, dramatic changes in glucose uptake upon pharmacologic. Dichloroacetate sodium dca is an inexpensive and simple chemical compound similar to combining vinegar and salt. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by dca. Background information in the 1920s, a german physiologist and nobel prize laureate, otto heinrich warburg, made an important discovery regarding the energy metabolism of cancer cells. It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. We tested whether the smallmolecule and orphan drug dichloroacetate dca can reverse this.
We tested this hypothesis by conducting the first doubleblind, randomized, control trial of dca in this disease. Citeseerx document details isaac councill, lee giles, pradeep teregowda. We show that the small molecule dichloroacetate inhibits a gatekeeping enzyme for glucose oxidation pyruvate dehydrogenase kinase and reverses the mitochondrial suppression in clear cell renal cell carcinoma, resulting in reductions in angiogenesis and tumor growth in. Dca appears to reactivate suppressed mitochondria in some types of oxygenstarved tumor cells, and thus promotes apoptosis. Dichloroacetate dca is a synthetic drug which is has been shown to kill cancer cells by taking advantage of cancers particular metabolic process and uses it against it. To determine whether human gbm could be a target for metabolic therapy with dca, we studied 49 freshly excised consecutive primary gbms 60% male, 48 11 years. Mitochondrial metabolism is an attractive target for cancer therapy. Inconclusion,thisstudyprovidesthe proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. Metabolic modulation of glioblastoma with dichloroacetate. However, epigenetic modulation is also important in metabolic decision. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. One of the candidates in this class of drugs being investigated is dichloroacetate dca, a molecule used for over 25 years in the treatment of children with inborn errors in mitochondrial function.
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