Cytotoxicity of natural and synthetic cannabinoids and their synergistic antiproliferative effects with cisplatin in human ovarian cancer cells.

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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Chen, Li, Liu, Ni, Deng, He, Wu, Wan, Seeram, Liu, Ma and Zhu.)