Rapamycin enhanced the antitumor efficacy of oxaliplatin in cisplatin-resistant ovarian cancer cells A2780cis both in vitro and in vivo

Abstract

Objective: This study aimed to investigate the efficacy of combination of rapamycin, an mammalian target of rapamycin (mTOR) inhibitor for treating rejection after organ transplantation, and oxaliplatin, a third-generation of platinum drug usually used to treat chemoresistant or progressive ovarian cancer, in cisplatin-resistant ovarian carcinoma cells A2780cis.Methods/Materials: Expressions of mTOR and its target molecules p70S6K and 4E-BP1 were determined in cisplatin-sensitive and -resistant cells A2780 and A2780cis, respectively, using Western blotting. Proliferation of A2780cis exposure to oxaliplatin or oxaliplatin plus rapamycin was examined using MTT assay in vitro as well as a nude mice model in vivo. Cell apoptosis and proapoptosis proteins including caspase-8 and -3 and PARP were determined using flow cytometry and Western blotting.Results: We found that A2780cis cells had partial cross-resistance between cisplatin and oxaliplatin. The levels of phosphorylated mTOR (p-mTOR), p70S6K, and 4E-BP1 were significantly increased in A2780cis cells compared to A2780 cells, which might be implicated in cisplatin-induced chemoresistance. Rapamycin obviously enhanced the inhibitory effect of oxaliplatin on the growth of A2780cis both in vitro and in vivo. Rapamycin slightly induced cell apoptosis but significantly enhanced the effect of oxaliplatin in soliciting apoptosis of A2780cis cells, which might be ascribed to its ability in further increasing the levels of cleaved caspase-8 and -3 and PARP induced by oxaliplatin.Conclusion: These results suggested that combination of oxaliplatin and rapamycin enhanced the antitumour efficacy of oxaliplatin in A2780cis cells and therefore might have a role in treating cisplatin-resistant ovarian carcinoma.