Metabolic modulation pyruvate dehydrogenase kinase warburg effect dichloroacetate abstract background. 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. Repurposing dichloroacetate for the treatment of women. Dca increases the flux of pyruvate into the mitochondria by inhibiting the pyruvate dehydrogenase kinase and promotes glucose oxidation over glycolysis. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was. Medline is the largest medical database in the world, and. The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Gscs were established from tumors formed by ink4aarfnull, hras v12expressing gliomainitiating cells that differed in extracellular acidification potential. Dichloroacetate or dca as it is commonly called as been in use for years to treat a rare genetic disorder called lactic. Dec 17, 2019 endometriosis is a chronic pain condition affecting. Endometriosis is a chronic pain condition affecting. Glioblastoma gbm is the most common and malignant primary brain tumor.
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. It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Dichloroacetate is an antimetabolite that antagonizes. Like normal cells, tumor cells need to convert sugar to energy to survive. Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism. We tested whether the smallmolecule and orphan drug dichloroacetate dca can reverse this. The average survival rate postdiagnosis is only of 14. New for 2019 glioblastoma prognosis treatment with dca. Dichloroacetate dca as a potential metabolic targeting therapy for cancer. Citeseerx document details isaac councill, lee giles, pradeep teregowda. Brain mri showing a large glioblastoma tumour with areas of necrosis within the tumour and significant brain oedema.
Cotreatment with dichloroacetate and omeprazole exhibits a. Recent studies of human orthotopic gbm in mice and in situ demonstrated gbm cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. Metabolic modulation of glioblastoma with dichloroacetate. Pinkd, katia carminesimmend, ronald moorea, john d lewisd. The structure of the molecule is similar to a combination of table salt and vinegar. Phase 1 trial of dichloroacetate dca in adults with.
Design we conducted an openlabel study of oral dca in 15 adults with recurrent who grade iii iv gliomas or metastases from a primary cancer outside the central nervous system. 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. Monochloroacetate mca, dichloroacetate dca, and trichloroacetate tca are chlorinated acetates that are formed during water disinfection processes. Metabolic modulation of glioblastoma with dichloroacetate medicor cancer center in canada is a cancer clinic currently offering dca therapy for its patients. Global metabolomic profiling identified an accumulation of several metabolic intermediaries of tryptophan metabolism in glioblastoma. It confirmed that dca is an effective anticancer drug for treating glioblastoma patients metabolic modulation of glioblstoma with dichloroacetate, science transltional medicine, vol 2, issue 31. It was originally used in cases of a rare disease called congenital lactic acidosis. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma bearing mice.
This means it is not a new drug and has been used safely in humans for decades. Hydroxyurea is the most commonly used cytoreductive agent. May 12, 2010 metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma. The small study proved that dca could be an essential missing part of the gbm treatment. A number of metabolic pathways that seem to be important for tumor growth are being touted as novel targets for anticancer drug development. The salts and esters of dichloroacetic acid are called. Bonnet et al have reported that treating cancer cells with dichloroacetate. Research article cancer metabolic modulation of glioblastoma with dichloroacetate e.
Chemical exchange saturation transfer cest is a novel mri contrast mechanism that is. Dualtargeting of aberrant glucose metabolism in glioblastoma. Nobuyuki fukui, kazunari yoshida, hideyuki saya, oltea sampetrean, metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model, neurooncology, volume 20. Repurposing dichloroacetate for the treatment of women with. We conducted a randomized control trial, followed by an openlabel study. The occurrence of side effects such as neurotoxicity as well as the suspicion of dca carcinogenicity still restricts the clinical use of dca. Metabolic heterogeneity and plasticity of glioma stem. It has published several case studies about the safety and effectiveness of dca. It is defined by the presence of endometriumlike tissue lesions outside the uterus, most commonly on the pelvic peritoneum.
In contrast to some other tumor types, aberrant glucose metabolism is an important component of gbm growth and chemoresistance. Under normal conditions, the material appears in powder form, white color and is soluble in water. If youre interested in the study, please read more below. Inconclusion,thisstudyprovidesthe proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells.
Dichloroacetate treatment for mitochondrial cytopathy. 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. We tested whether the smallmolecule and orphan drug dichloroacetate dca can reverse this cancerspecific metabolic and mitochondrial remodeling in glioblastoma. Hopefully, more and more studies will be directed towards this alternative view of dealing with glioblastoma. The first formal human cancer research using dca was published in may 2010. Along with that if my platelets are above 100,000 i will get a once every three weeks infusion of cpt11. Studies from this application of dca indicate mild to. Metabolic abnormalities in glioblastoma and metabolic strategies to. This metabolicremodeling isaccompaniedbymitochondrialhyperpolarization. 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. Recent reports demonstrate that the antidiabetic drug metformin enhances the damaging oxidative stress associated with dca treatment in cancer cells. However, in the last years, the number of reports supporting dca. Dichloroacetate induced intracellular acidification in. Modulation of tumor phi may influence proliferation, apoptosis, chemotherapy resistance, and thermosensitivity.
Nov 16, 2017 intracellular ph phi plays an important role in the maintenance of normal cell function, and is maintained within a narrow range by the activity of transporters located at the plasma membrane. Aug 02, 2011 9 michelakis ed sutendra g dromparis p webster l haromy a niven e maguire c gammer tl mackey jr fulton d abdulkarim b mcmurtry ms petruk kc metabolic modulation of glioblastoma with dichloroacetate sci transl med 2010 231ra34. Introduction glioblastoma multiforme gbm is an aggressive primary brain tumor that exhibits extremely poor responses to approved therapies 1. Dichloroacetate induces apoptosis in endometrial cancer cells. 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. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. I was diagnosed 12910 and so far my mris have all shown that the tumor is stable.
Sensitization of glioblastoma cells to irradiation by. Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors. Clearcell renal cell carcinoma ccrcc exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. Metabolic modulation of clearcell renal cell carcinoma with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase. Dca dichloroacetate frequently asked questions background. All endometriosis drug approvals to date have been contraceptive, limiting their use in women of childbearing age. Dichloroacetate dca is a synthetic halogenated organic acid which has been used in rare diseases like congenital lactic acidosis. In addition to the clinical and neuropathology reports, we confirmed gbm identity with fig. This study also observed that apoptosis was further increased in the glioblastoma stem. Study of the safety and efficacy of dichloroacetate dca in. Complex i inhibition augments dichloroacetate cytotoxicity through. Metabolic characteristics of gscs were determined by measurement of glucose, oxygen, and glutamine uptake, atp content, and lactate production. Data were analyzed for each patient from the time they began treatment through.
The robust glycolytic metabolism of glioblastoma multiforme gbm has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate dca. Michelakis ed, sutendra g, dromparis p, webster l, haromy a, niven e, maguire c, gammer tl, mackey jr, fulton d, et al. Sep 11, 2018 metabolic modulation of glioblastoma with dichloroacetate. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma. In clinical oncology, dca emerged as a promising safe. Background recurrent malignant brain tumors rmbts carry a poor prognosis. Like the other chloroacetic acids, it has various practical applications. Cancer metabolic modulation of glioblastoma with dichloroacetate e. Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model. 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.
Dca results in daily life from water chlorination and is also a promising drug treatment for treating mitochondrial diseases, pulmonary arterial hypertension and cancer. 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. Glioblastoma gbm is the most aggressive and common form of primary brain tumour characterized by fast proliferation, high invasion, and resistance to current standard treatment. Dec 19, 2019 dichloroacetate sodium dca is an inexpensive and simple chemical compound similar to combining vinegar and salt. Effects of dichloroacetate as single agent or in combination. Targeting tumor metabolism brain tumor brain cancer. Medline is the largest medical database in the world, and contains information on published dca research.
Sep 10, 2018 rasm uthmani pdf polisitemia vera finazzi g, barbui t. Pdf metabolic modulation of glioblastoma with dichloroacetate. Differential expression of hif1 in glioblastoma multiforme and anaplastic. 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. The purpose of this study is to evaluate the safety and tolerability of oral dichloroacetate dca in the treatment of recurrent malignant brain tumors rmbts. Metabolic heterogeneity and plasticity of glioma stem cells. May 12, 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.
A common fea ture among all gbm and most solid tumor cells is met. Webster l, haromy a, niven e, maguire c, gammer tl, mackey jr, fulton d, et al. Potential glioblastoma cancer cure with the help of dca. Metabolic modulation of glioblastoma with dichloroacetate science translational medicine, 2 31, 31 doi. 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. Pdf solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a. The robust glycolytic metabolism of glioblastoma multiforme gbm has proven them. Dichloroacetate dca as a potential metabolictargeting. Sensitization of glioblastoma cells to irradiation by modulating the. 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. 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. Metabolic modulation of clearcell renal cell carcinoma. Further research to determine how well dca works against various cancers within the human body is ongoing. I am currently taking a low dose of temodar six weeks on and three weeks off 140 m.
Effects of dichloroacetate as single agent or in combination with gw6471 and metformin in paraganglioma cells. Dichloroacetic acid dca, sometimes called bichloroacetic acid bca, is the chemical compound with formula c h cl 2 cooh. Bonnet et al have reported that treating cancer cells with dichloroacetate dca, an approved treatment for congenital lactic acidosis, reverses the warburg effect and inhibits tumor growth 3,4,68. Complex i inhibition augments dichloroacetate cytotoxicity. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field. Modulation of oxidative stress alters dca cytotoxicity towards vmm3 cells.
Dca dichloroacetate sodium treatment for cancer cancer. Metabolic modulation as a novel cancer treatment heart and. A small but mechanistic earlyphase trial of oral dca in patients with gbm showed that the mechanism described in animal models operates in human tumors 18 x 18 michelakis, e. More recently in the era of targeted therapy, dramatic changes in glucose uptake upon. Metabolic modulation of clearcell renal cell carcinoma with. 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. On of the more promising glioblastoma and malignant astrocytoma treatment options introduces a very old compound called 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. No controlled clinical trials of dca are available.
Dichloroacetate dca activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Brain mri showing a large glioblastoma tumour with areas of necrosis within the. Several publications demonstrated that dca works in a variety of cancers. Therapeutic modulation of cancer metabolism with dichloroacetate. Use of oral dichloroacetate for palliation of leg pain. Expression of hif1alpha and inos in astrocytic gliomas. We sought to elucidate the role of metformins reported.
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