Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo
Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo
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DOI：
10.4161/cbt.22003
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Senekowitsch-Schmidtke, Reingard
中科院分区：
文献类型：
--
作者：
Feuerecker, Benedikt;Pirsig, Sabine;Senekowitsch-Schmidtke, Reingard
即使在氧气存在的情况下，癌细胞也会优先将葡萄糖转化为乳酸(有氧糖酵解-Warburg效应)。癌症治疗的新概念旨在抑制有氧糖酵解。丙酮酸脱氢酶将丙酮酸转化为乙酰辅酶A，从而防止乳酸的形成。因此，本研究的目的是评估能够激活癌细胞中丙酮酸脱氢酶的化合物。研究了丙酮酸脱氢酶的可能激活剂(R)-(+)-α-硫辛酸(LPA)和二氯乙酸酯(DCA)对有氧糖酵解的抑制和诱导细胞死亡的作用。观察两种化合物对细胞存活/增殖(WST-1法)、[18F]-FDG摄取、乳酸生成和诱导细胞凋亡(流式细胞仪检测caspase-3)的影响。此外，NMRI nu/nu小鼠接种S.C.从第7天开始，每天给SkBr3细胞注射LPA(18.5 mg/kg)，连续4周。肿瘤生长用滑动卡尺测量，并通过[18F]-FDG-PET监测。对治疗后的残留肿瘤进行了组织病理学检查。这些数据表明，在所有研究的细胞系中，LPA可以减少(1)细胞的存活/增殖，(2)摄取[18F]-FDG和(3)乳酸的产生和增加细胞的凋亡。相比之下，DCA几乎没有效果。在小鼠S.C.异种移植模型中。SkBr3细胞，每天用LPA治疗延缓肿瘤进展。因此，LPA似乎是一种很有前途的癌症治疗化合物。
Cancer cells convert glucose preferentially to lactate even in the presence of oxygen (aerobic glycolysis-Warburg effect). New concepts in cancer treatment aim at inhibition of aerobic glycolysis. Pyruvate dehydrogenase converts pyruvate to acetylCoA thus preventing lactate formation. Therefore, the aim of this study was to evaluate compounds that could activate pyruvate dehydrogenase in cancer cells. We investigated the effects of (R)-(+)-alpha-lipoic acid (LPA) and dichloroacetate (DCA), possible activators of pyruvate dehydrogenase, on suppression of aerobic glycolysis and induction of cell death.The neuroblastoma cell lines Kelly, SK-N-SH, Neuro-2a and the breast cancer cell line SkBr3 were incubated with different concentrations (0.1-30 mM) of LPA and DCA. The effects of both compounds on cell viability/proliferation (WST-1 assay), [18F]-FDG uptake, lactate production and induction of apoptosis (flow cytometric detection of caspase-3) were evaluated. Furthermore, NMRI nu/nu mice that had been inoculated s.c. with SkBr3 cells were treated daily for four weeks with LPA (i.p, 18.5 mg/kg) starting at day 7 p.i. Tumor development was measured with a sliding calliper and monitored via [18F]-FDG-PET. Residual tumors after therapy were examined histopathologically.These data suggests that LPA can reduce (1) cell viability/proliferation, (2) uptake of [18F]-FDG and (3) lactate production and increase apoptosis in all investigated cell lines. In contrast, DCA was almost ineffective. In the mouse xenograft model with s.c. SkBr3 cells, daily treatment with LPA retarded tumor progression. Therefore, LPA seems to be a promising compound for cancer treatment.