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...

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Bibliographic Details
Published in:European journal of pharmacology 2010-04, Vol.632 (1), p.7-13
Main Authors: Lee, Chung Soo, Kim, Yun Jeong, Jang, Eun-Ra, Myung, Soon Chul, Kim, Wonyong
Format: Article
Language:English
Subjects:
Adenocarcinoma - pathology
Akt inhibitor
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - physiology
Apoptosis-related protein
Biological and medical sciences
Carboplatin
Carboplatin - pharmacology
Cell death
Cell Death - drug effects
Cell Line, Tumor
Epithelial ovarian carcinoma cell
Female
Female genital diseases
Gynecology. Andrology. Obstetrics
Humans
Medical sciences
Ovarian Neoplasms - pathology
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-akt - metabolism
Tumors
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Summary: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.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2010.01.004