Metabolic Modulation of Glioblastoma with Dichloroacetate
Metabolic Modulation of Glioblastoma with Dichloroacetate
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DOI：
10.1126/scitranslmed.3000677
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发表时间：
2010-05-12
影响因子：
17.1
通讯作者：
Petruk, K. C.
中科院分区：
文献类型：
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作者：
Michelakis, E. D.;Sutendra, G.;Petruk, K. C.
实体瘤，包括侵袭性原发性脑癌多形性胶质母细胞瘤，对细胞死亡产生抗性，部分原因是线粒体氧化磷酸化转变为细胞质糖酵解。这种代谢重塑伴随着线粒体超极化。我们测试了小分子和孤儿药二氯醋酸盐（DCA）是否可以逆转胶质母细胞瘤中这种癌症特异性代谢和线粒体重塑。从49例患者新鲜分离的胶质母细胞瘤显示线粒体超极化，这是迅速逆转DCA。在一项针对5名胶质母细胞瘤患者的单独实验中，我们前瞻性地获得了基线和系列肿瘤组织，开发了胶质母细胞瘤和假定胶质母细胞瘤干细胞（CD133（+），巢蛋白（+）细胞）的患者特异性细胞系，并对每位患者进行了长达15个月的口服DCA治疗。在体外和体内，DCA使线粒体去极化，增加线粒体活性氧，并诱导GBM细胞以及推定的GBM干细胞的凋亡。DCA治疗还抑制缺氧诱导因子-1 α，促进p53激活，并抑制体内和体外血管生成。剂量限制性毒性为剂量依赖性、可逆性周围神经病变，无血液学、肝、肾或心脏毒性。在不引起周围神经病变的剂量和足以抑制DCA靶酶丙酮酸脱氢酶激酶II（在所有胶质母细胞瘤中高度表达）的DCA血清浓度下，存在临床疗效迹象。代谢调节可能是治疗胶质母细胞瘤的一种可行的治疗方法。
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 stemcells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1 alpha, 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.