Cytotoxicity of natural and synthetic cannabinoids and their synergistic antiproliferative effects with cisplatin in human ovarian cancer cells
Ying Chen, Huifang Li, Jia‐Bao Liu, Jie Ni, Qicheng Deng, Haotian He, Panpan Wu, Yinsheng Wan, Navindra P. Seeram, Chang Liu, Hang Ma, Weipei Zhu
Abstract
Introduction Cannabinoids are reported to suppress the growth of ovarian cancer cells, but it is unclear whether structural modifications can improve their cytotoxic effects. Methods Herein, an investigation into the antiproliferative effects of natural cannabinoids on human ovarian cancer Caov-3 cells identified cannabidiol (CBD) as the most promising cannabinoid. Furthermore, chemical modifications of CBD yielded a group of derivatives with enhanced cytotoxicity in Caov-3 cells. Results Two CBD piperazinyl derivatives ( 19 and 21 ) showed augmented antiproliferative effects with an IC 50 of 5.5 and 4.1 µM, respectively, compared to CBD’s IC 50 of 22.9 µM. Further studies suggest that modulation of apoptosis and ferroptosis may contribute to the cytotoxic effects of CBD and its derivatives. In addition, CBD and its derivatives ( 19 and 21 ) were explored for their potential synergistic antiproliferative effects in combination with chemotherapeutic agent cisplatin. Compounds 19 or 21 (5 µM) combined with cisplatin (1 µM) showed a synergistic effect with a combination index of 0.23 and 0.72, respectively. This effect was supported by elevated levels of reactive oxygen species in Caov-3 cells treated with cisplatin combined with 19 or 21 . Discussion Findings from this study suggest that CBD derivatives with enhanced antiproliferative effects may exert synergistic effects with chemotherapeutic drugs, providing insight into the development of cannabinoid-based adjuvant agents for the management of ovarian cancer.