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