Inhibition of paclitaxel resistance and apoptosis induction by cucurbitacin B in ovarian carcinoma cells

摘要

Ovarian cancer is the leading cause of mortality among all gynecological malignancies. Drug resistance is a cause of ovarian cancer recurrence and low rate of overall survival. There is a requirement for more effective treatment approaches. Cucurbitacin B (CuB) is an antineoplastic agent derived from traditional Chinese medicinal herbs. Its activity against paclitaxel-resistant human ovarian cancer cells has, however, not yet been established. The purpose of the present study was to investigate the effect and mechanism of CuB on human paclitaxel-resistant ovarian cancer A2780/Taxol cells. Cell viability was evaluated by a cell counting assay, while cell cycle arrest and apoptosis were assessed by microscopy and flow cytometry, and proteins associated with apoptotic pathways and drug resistance were evaluated by western blotting. The present results demonstrated that CuB exerts dose- and time-dependent cytotoxicity against the ovarian cancer A2780 cell line, with half-maximal inhibitory concentration (IC50) values 0.48, 0.25 and 0.21 µM following 24, 48 and 72 h of incubation, respectively. Compared with its sensitive counterpart, A2780, paclitaxel-resistant A2780/Taxol cells had almost identical IC50 values. Cell cycle analysis demonstrated that treatment with CuB may induce cell cycle arrest at the G2/M phase of the cell cycle in the two cell lines. As revealed by Annexin V/propidium iodide-labeled flow cytometry and Hoechst 33258 staining, CuB-induced apoptosis was accompanied by activation of caspase-3 and downregulation of B-cell lymphoma-2. Western blotting demonstrated that CuB may enhance the expression of p53 and p21 in the two cell lines. CuB may also downregulate the expression of P-glycoprotein. These results indicate that CuB may exert a therapeutic effect on paclitaxel-resistant human ovarian cancer.