Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species

ObjectiveThe acquired resistance to platinum-based drugs has become an obstacle in the management of ovarian cancer. We investigated the apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, in platinum-resistant human ovarian cancer cells, along with the molecular mechanism of action.MethodsCostunolide and cisplatin were examined in platinum-resistant human ovarian cancer cells. MTT assay for cell viability, PI staining for cell cycle profiling, and Annexin V assay for apoptosis analysis. ROS production and protein expression was assessed by H2DCFDA staining and Western blotting, respectively. Combination effect was determined using the Combination Index (CI) method.ResultsIt was found that costunolide is more potent than cisplatin in inhibiting cell growth in three platinum-resistant ovarian cancer cell lines (MPSC1PT, A2780PT, and SKOV3PT). Costunolide induced apoptosis of platinum-resistant cells in a time- and dose-dependent manner and suppressed tumor growth in SKOV3PT-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, -8, and -9. Pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Additionally, the antioxidant N-acetyl-L-cysteine (NAC) significantly attenuated the costunolide-induced production of ROS, activation of caspases, down-regulation of Bcl-2, and apoptosis in platinum-resistant ovarian cancer cells. Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.ConclusionsTaken together, these data suggest that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancer.

► Costunolide induces apoptosis of platinum-resistant ovarian cancer cells.
► Costunolide increases ROS production and caspases activation.
► Bcl-2 expression is downregulated by costunolide.
► Costunolide acts synergistically with cisplatin.