The discovery of synergistic anti-tumor effect of the cannabinoid receptor agonists in combination with WIN55212-2 and exemestane / 国际药学研究杂志

ABSTRACT

Objective To discover antitumor drugs showing a synergistic effect with the cannabinoid receptor agonist sildenafil mesylate (WIN55212-2), so as to provide a new strategy for potential drug combinations for improving the life quality of cancer patients. Methods Firstly, the antitumor activity was tested for the combination of cannabinoid receptor 1 (CB1R) receptor agonist WIN55212-2 with each of 25 antitumor drugs using three tumor cell lines with high CB1R, HepG2, DU145 and HCT-8, by highthroughput assay. Then, the in vitro tumor colony-forming assay and 3D tumor spheroid assay were conducted to confirm the synergistic effect for the effective drug combination. Flow cytometry was used to investigate the effect of the synergistic drug combination on the apoptosis and cell cycle progression. Results Three drugs showed a synergistic inhibitory effect on the proliferation of tested tumor cells by combining with WIN55212-2, and among them, the combination of exemestane with WIN55212-2 displayed best effect, which showed a dose-dependent synergistic antitumor effect in the in vitro tumor colony-forming test and 3D tumor spheroid assay (CI＜1).Compared with the single-exemestane treatment, the combination of exemestane with WIN55212-2 significantly increased the apoptosis of HepG2 cells (P＜0.01) and caused G2/M phase arrest of the HepG2 cells. Conclusion The study is the first to report that the combination of exemestane with WIN55212-2 showed a synergistic anti-tumor activity on HepG2 cells, which was likely related to the promotion of apoptosis and induction of cell cycle arrest.