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

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.

Cannabinoid receptor agonist protects cultured dopaminergic neurons from the death by the proteasomal dysfunction / 대한해부학회지

Cannabinoids have been proposed to possess neuroprotective properties; though their mechanism of action remains contentious, they are posited to prevent neurodegenerative disorders, including Parkinson's disease, the pathogenesis of which has not been established. Recent studies have demonstrated that induction of proteasomal dysfunction in animal models results in a phenotype similar to Parkinson's disease. Here, we investigated the neuroprotective function of a synthetic cannabinoid-receptor agonist (WIN55.212.2) in dopaminergic neuronal death induced by a proteasomal synthase inhibitor (PSI), additionally testing the hypothesis that WIN55.212.2 modulates cytoplasmic accumulation of parkin and alpha-synuclein, a key feature of proteasomal dysfunction in Parkinson's. WIN55.212.2 protects PC12 cells from PSI-induced cytotoxicity, concomitantly inhibiting PSI-induced polyADP ribose polymerase expression and activation of caspase-3. While PSI induces cytoplasmic accumulation of alpha-synuclein and parkin, WIN55.212.2 counters these effects. Interestingly, however, while PSI induces the activation and nuclear translocalization of nuclear factor kappaB, WIN55.212.2 potentiates this effect. These data are suggestive that WIN55.212.2 might confer a neuroprotective benefit in PSI-induced proteasomal dysfunction, and could further protect against neuronal degeneration stemming from cytoplasmic accumulation of alpha-synuclein and parkin. These results indicate that WIN55.212.2 may be a candidate for treatment of neurodegenerative diseases, including Parkinson's disease.