Dual regulation of Akt and glutathione caused by isoalantolactone effectively triggers human ovarian cancer cell apoptosis.
Dual regulation of Akt and glutathione caused by isoalantolactone effectively triggers human ovarian cancer cell apoptosis.
复制标题
异木聚糖内酯对 Akt 和谷胱甘肽的双重调节可有效触发人卵巢癌细胞凋亡。
DOI：
10.3724/abbs.2023003
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发表时间：
2023-02-25
影响因子：
3.7
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Xie Z;Xu J;Xiao D;Lei J;Yu J
卵巢癌是妇科肿瘤致死的主要原因之一。异丙内酯(Isoalantolacone，IL)广泛存在于多种药用植物中，具有多种生物活性，其抗卵巢癌作用机制有待进一步研究。在这里，我们发现IL通过引起G2/M期阻滞和诱导细胞凋亡来抑制SKOV-3和OVCAR-3细胞的增殖。此外，IL还可降低SKOV-3细胞内谷胱甘肽(GSH)水平，并诱导ROS的产生。此外，IL诱导Akt失活，这是IL的细胞毒性所必需的。此外，Akt的过表达可减弱IL诱导的生长抑制和ROS的产生。补充GSH可适度增加磷酸化Akt的表达。进一步的研究表明，用谷胱甘肽生物合成抑制剂L-丁硫氨酸-亚磺胺(GSH生物合成抑制剂)预处理可恢复AKT介导的IL抑制生长的减弱。此外，IL和Wortmannin(Akt途径的抑制剂)共同处理可增加GSH生物合成前体N-乙酰-L-半胱氨酸所减弱的生长抑制。这些结果表明，IL诱导的Akt失活和GSH水平下调是相互关联的。综上所述，联合靶向Akt和GSH是一种有效的肿瘤治疗策略，IL可能是一种有前途的抗癌药物，值得进一步开发。
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.