能杀死癌细胞的廉价药二氯乙酸盐
2010-06-06 抗癌健康网
专注健康 关爱生命 加拿大艾伯塔大学研究人员在新一期美国《科学—转化医学》杂志网络版上发表报告说，他们让5名恶性胶质瘤（一种脑癌）患者服用了适量的二氯乙酸盐。结果发现，在二氯乙酸盐的作用下，患者肿瘤组织的新陈代谢发生了变化，其中4名患者的肿瘤在治疗后的15个月里没有进一步发展。对从这些患者身上提取的癌细胞的研究显示，二氯乙酸盐杀死了癌细胞。
研究报告的主要作者、加拿大艾伯塔大学的米切拉基斯说，可以初步得出二氯乙酸盐对某些患者可能是安全的和有临床效果的结论。他同时指出，由于研究规模很小，还不能得出更多的结论。
生物谷推荐原文出处：
Sci Transl Med DOI: 10.1126/scitranslmed.3000677
Metabolic Modulation of Glioblastoma with Dichloroacetate
E. D. Michelakis1,*, G. Sutendra1, P. Dromparis1, L. Webster1, A. Haromy1, E. Niven2, C. Maguire2, T.-L. Gammer1, J. R. Mackey3, D. Fulton3, B. Abdulkarim3, M. S. McMurtry1 and K. C. Petruk4
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.
研究报告的主要作者、加拿大艾伯塔大学的米切拉基斯说，可以初步得出二氯乙酸盐对某些患者可能是安全的和有临床效果的结论。他同时指出，由于研究规模很小，还不能得出更多的结论。
生物谷推荐原文出处：
Sci Transl Med DOI: 10.1126/scitranslmed.3000677
Metabolic Modulation of Glioblastoma with Dichloroacetate
E. D. Michelakis1,*, G. Sutendra1, P. Dromparis1, L. Webster1, A. Haromy1, E. Niven2, C. Maguire2, T.-L. Gammer1, J. R. Mackey3, D. Fulton3, B. Abdulkarim3, M. S. McMurtry1 and K. C. Petruk4
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.
