Dual regulation of Akt and glutathione caused by isoalantolactone effectively triggers human ovarian cancer cell apoptosis

Ovarian cancer is one of leading causes of cancer death in gynecological tumor. Isoalantolactone (IL), present in several medicinal plants, exhibits various biological activities, and its mechanism underlying anti-ovarian cancer activity needs to be further investigated. Here, we find that IL inhibits the proliferation of SKOV-3 and OVCAR-3 cells by causing G2/M phase arrest and inducing apoptosis. Moreover, IL decreases intracellular glutathione (GSH) level, and induces reactive oxygen species (ROS) generation in SKOV-3 cells. Furthermore, IL induces inactivation of Akt which is required for the cytotoxicity of IL. In addition, overexpression of Akt attenuates the IL-induced growth inhibition and ROS generation. GSH supplementation moderately increases the expression of phospho-Akt. Further investigation reveals that pretreatment with L-buthionine-sulfoximine (a GSH biosynthesis inhibitor) restores the Akt-mediated attenuation of growth inhibition induced by IL. Moreover, co-treatment with IL and wortmannin (an Akt pathway inhibitor) increases the growth inhibition attenuated by pretreatment with N-acetyl-L-cysteine (a precursor for GSH biosynthesis). These results indicate that inactivation of Akt and downregulation of GSH level induced by IL are related to each other. In conclusion, combined targeting Akt and GSH is an effective strategy for cancer therapy and IL can be a promising anticancer agent for further exploration.