Akt inhibitor enhances apoptotic effect of carboplatin on human epithelial ovarian carcinoma cell lines.
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.
Lee
Chung Soo
CS
Department of Pharmacology, Chung-Ang University, Seoul, South Korea. leecs@cau.ac.kr
Kim
Yun Jeong
YJ
Jang
Eun-Ra
ER
Myung
Soon Chul
SC
Kim
Wonyong
W
D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016190:Carboplatin / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D000970:Antineoplastic Agents; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt