Rapamycin-topotecan combination exhibited enhanced antitumor efficacy compared to topotecan used alone in cisplatin-resistant ovarian cancer cells
Abstract:
The present study aimed to investigate the antitumor efficacy of combination of topotecan with rapamycin, a mTOR inhibitor, in cisplatin-resistant ovarian cancer cells A2780cis and COC1/DDP. Expressions of mTOR and its target molecules p70S6K and 4E-BP1 were determined in A2780cis and COC1/DDP and the parental cells A2780 and COC1 that are sensitive to cisplatin using Western blotting. Cell proliferation was examined using MTT assay in vitro and a nude mouse model in vivo, respectively. Cell apoptosis and the relevant proteins were determined by flow cytometry and Western blotting. We found that the levels of phosphorylated mTOR, p70S6K, and 4E-BP1 were obviously higher in A2780cis and COC1/DDP cells than that in A2780 and COC1 cells. Pretreatment with rapamycin significantly enhanced the effects of topotecan in suppressing cell proliferation and soliciting cell apoptosis in A2780cis and COC1/DDP cells. Cells that were sequentially exposed to rapamycin and topotecan had significantly higher levels of cleaved caspase-8, -3, and PARP compared to those treated with topotecan alone. Mice co-administered rapamycin and topotecan had significantly decreased terminal tumor burden without additional loss of bodyweight compared to the mice received topotecan alone. The results suggested that rapamycin sensitized A2780cis and COC1/DDP cells to topotecan-induced apoptosis and rapamycin-topotecan combination might have a value in treatment of cisplatin-resistant ovarian cancer.