发现具有强大抗卵巢癌干细胞活性和 STAT3 抑制作用的半合成鬼臼毒素衍生物。
Discovery of semisynthetic celastrol derivatives exhibiting potent anti-ovarian cancer stem cell activity and STAT3 inhibition.
机构信息
Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, 252000, PR China.
Central Laboratory, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, PR China.
出版信息
Chem Biol Interact. 2022 Oct 1;366:110172. doi: 10.1016/j.cbi.2022.110172. Epub 2022 Sep 9.
The hallmark of ovarian cancer is its high mortality rate attributed to the existence of cancer stem cells (CSCs) subpopulations which result in therapy recurrence and metastasis. A series of C-29-substituted and/or different A/B ring of celastrol derivatives were synthesized and displayed potential inhibition against ovarian cancer cells SKOV3, A2780 and OVCAR3. Among them, compound 6c exhibited the most potent anti-proliferative activity and selectivity, gave superior anti-CSC effects through inhibition of the sphere formation and downregulation of the percentage of CD44CD24 and ALDH cells. Further mechanism research demonstrated that compound 6c could attenuate the expression of STAT3 and p-STAT3. The results suggested that the inhibition of celastrol derivative 6c on ovarian cancer cells may be related to resistance to cancer stem-like characters and regulation of STAT3 pathway.
卵巢癌的标志是其高死亡率，这归因于癌症干细胞（CSC）亚群的存在，导致治疗复发和转移。一系列 C-29 取代和/或不同 A/B 环的雷公藤红素衍生物被合成，并显示出对卵巢癌细胞 SKOV3、A2780 和 OVCAR3 的潜在抑制作用。其中，化合物 6c 表现出最强的抗增殖活性和选择性，通过抑制球体形成和下调 CD44CD24 和 ALDH 细胞的比例，表现出优异的抗 CSC 作用。进一步的机制研究表明，化合物 6c 可以减弱 STAT3 和 p-STAT3 的表达。结果表明，雷公藤红素衍生物 6c 对卵巢癌细胞的抑制作用可能与抵抗癌干细胞样特征和调节 STAT3 通路有关。
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