Department of Pharmacology, Chung-Ang University, Seoul, South Korea.
Eur J Pharmacol. 2010 Apr 25;632(1-3):7-13. doi: 10.1016/j.ejphar.2010.01.004. Epub 2010 Jan 21.
Carboplatin and Akt inhibitor have been shown to induce apoptosis in cancer cells. However, the combined effect of Akt inhibitor on the apoptotic effect of carboplatin in epithelial ovarian cancer cells remains uncertain. In the respect of the induction of cell death signaling pathways, we assessed the combined effect of Akt inhibitor on the carboplatin toxicity in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Carboplatin and Akt inhibitor induced nuclear damage, decreased Bid and Bcl-2 protein levels, induced cytochrome c release, activated caspase-3 and increased tumor suppressor p53 levels. Carboplatin increased in Bax levels, whereas Akt inhibitor decreased Bax levels. Akt inhibitor enhanced the carboplatin-induced apoptosis-related protein activation and cell death. Combination of carboplatin and Akt inhibitor-induced cell viability loss was reduced by selective inhibitors of caspase-8, -9 and -3. The results suggest that Akt inhibitor may enhance a carboplatin toxicity against ovarian carcinoma cell lines by increasing activation of the caspase-8 and Bid pathway as well as activation of the mitochondria-mediated apoptotic pathway, leading to mitochondrial cytochrome c release and subsequent caspase-3 activation. Combination of carboplatin and Akt inhibitor may provide a therapeutic benefit against ovarian adenocarcinoma.
卡铂和 Akt 抑制剂已被证明可诱导癌细胞凋亡。然而，Akt 抑制剂对上皮性卵巢癌细胞中卡铂的促凋亡作用的联合效应尚不确定。在细胞死亡信号通路的诱导方面，我们评估了 Akt 抑制剂对人上皮性卵巢癌细胞系 OVCAR-3 和 SK-OV-3 中卡铂毒性的联合效应。卡铂和 Akt 抑制剂诱导核损伤，降低 Bid 和 Bcl-2 蛋白水平，诱导细胞色素 c 释放，激活 caspase-3 并增加肿瘤抑制因子 p53 水平。卡铂增加 Bax 水平，而 Akt 抑制剂降低 Bax 水平。Akt 抑制剂增强了卡铂诱导的与细胞凋亡相关的蛋白激活和细胞死亡。特异性 caspase-8、-9 和 -3 的抑制剂可降低卡铂和 Akt 抑制剂诱导的细胞活力丧失。结果表明，Akt 抑制剂可能通过增加 caspase-8 和 Bid 途径以及线粒体介导的凋亡途径的激活，导致线粒体细胞色素 c 释放和随后的 caspase-3 激活，从而增强卡铂对卵巢癌细胞系的毒性。卡铂和 Akt 抑制剂的联合可能为治疗卵巢腺癌提供治疗益处。
