Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B.

Ovarian cancer is the most deadly gynecological cancer. The first line in treatment is platinum-based drugs. However, most patients suffer from tumor recurrence, characterized by resistance to cisplatin. A plausible approach to address the tumor resistance is to co-administer the chemotherapeutic agents along with natural products to offer a synergistic effect and optimize the dosage regimen. Cucurbitacin B is a natural product and displays antitumor activity against a wide array of cancer cell lines. The aim of this work is to determine the antitumor activity against ovarian cancer cell line (A2780) and possible sensitization activity on cisplatin-resistant cell line (A2780CP) in 2D and 3D culture model. 3D spheroids were generated from A2780CP cell line. A2780, A2780CP, and the spheroids were treated with cucurbitacin B, cisplatin alone, or pretreated with cucurbitacin B followed by cisplatin. The viability, cell cycle, and apoptosis were analyzed. Level of ROS and total glutathione was measured. In this study, cucurbitacin B showed cytotoxicity against the ovarian cancer cell lines, and pretreatment of A2780CP cells leads to a significant increase in the cytotoxicity of cisplatin. The mechanism behind the sensitization effect was dependent in part on the depletion of the total glutathione, an increase in ROS through a decrease in the level of dual-specificity tyrosine-regulated kinase (Dyrk1B), decrease in pERK1/2 and pSTAT3 level. The viability of spheroids treated with a combination of cisplatin and cucurbitacin B were significantly decreased. The resulting data shows that cucurbitacin B is a promising chemosensitizer for the cisplatin-resistant ovarian cancer.