Search

Recent researches have shown that estrogen receptor-β (ERβ) activator may be a potent anticancer agent for prostate cancer (PCa), and our previous study also indicated that dioscin can upregulate the expression of ERβ in MC3T3-E1 cell. In the present work, the activity and mechanism of dioscin, a natural product, against PCa were investigated. The results showed that dioscin markedly inhibited cell viability, colony formation, motility and induced apoptosis in PC3 cells. Moreover, dioscin disrupted the formation of PC3 cell-derived mammospheres and reduced aldehyde dehydrogenase (ALDH) level and the CD133+/CD44+ cells, indicating that dioscin had a potent inhibitory activity on prostate cancer stem cells (PCSCs). In vivo results also showed that dioscin significantly suppressed the tumor growth of PC3 cell xenografts in nude mice. Furthermore, mechanism investigation showed that dioscin markedly upregulated ERβ expression level, subsequently increased prolyl hydroxylase 2 level, decreased the levels of hypoxia-inducible factor-1α, vascular endothelial growth factor A and BMI-1, and thus induced cell apoptosis by regulating the expression levels of caspase-3 and Bcl-2 family proteins. In addition, transfection experiment of ERβ-siRNA further indicated that diosicn showed excellent activity against PCa in vitro and in vivo by increasing ERβ expression level. The co-immunoprecipitation (Co-IP) results further suggested that dioscin promoted the interaction of c-ABL and ERβ, but did not change c-ABL expression. Moreover, the molecular docking assay showed that dioscin processed powerful affinity toward to ERβ mainly through the strong hydrogen bonding and hydrophobic effects, and the actions of dioscin on ERβ activation and tumor cells inhibition were significantly weakened in the mutational (Phe-336, Phe-468) PC3 cells. Collectively, these findings proved that dioscin exerted efficient anti-PCa activity via activation of ERβ, which should be developed as an efficient candidate in clinical for treating this cancer in the future.

Dioscin exhibits a range of pharmacological actions but little is known of its effects on cisplatin (CDDP)-induced nephrotoxicity. Here, we have assessed the effects and the possible mechanisms of dioscin against CDDP-induced nephrotoxicity.We used an in vivo model of CDDP-induced nephrotoxicity in rats and mice and, in vitro, cultures of NRK-52E and HK-2 cells. The dual luciferase reporter assay was used to demonstrate modulation, by dioscin, of the targeting of sirtuin 1 (Sirt1) by microRNA (miR)-34a. Molecular docking assays were used to analyse the effects of dioscin with Sirt1, Keap1 and NF-κB.Dioscin attenuated cell damage in vitro and decreased renal injury in rats and mice, treated with CDDP. In terms of mechanisms, dioscin reversed CDDP-induced up-regulation of miR-34a and thus up-regulated Sirt1 levels. In addition, dioscin altered levels of haem oxygenase 1, glutathione-cysteine ligase subunits (GCLC, GCLM) and Keap1, along with increased nuclear translocation of Nrf2, thus decreasing oxidative stress. Also, dioscin affected levels of AP-1, COX-2, HMGB1, IκB-α, IL-1β, IL-6 and TNF-α and decreased the ratio of acetylated NF-κB and normal NF-κB, to suppress inflammation. From molecular docking assays, dioscin directly bound to Sirt1, Keap1 and NF-κBp65 by hydrogen bonding and/or hydrophobic interactions.Our results have linked CDDP-induced nephrotoxicity and the miR-34a/Sirt1 signalling pathway, which was modulated by dioscin. This natural product could be developed as a new candidate to alleviate CDDP-induced renal injury.