Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway.
Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway.
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DOI：
10.1016/j.ejmech.2018.08.036
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发表时间：
2018-09
影响因子：
6.7
通讯作者：
Gaofei Wei;Jiahong Sun;Zhuang Hou;Weijing Luan;Shuai Wang;Shanshan Cui;M. Cheng;Yang Liu
中科院分区：
文献类型：
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作者：
Gaofei Wei;Jiahong Sun;Zhuang Hou;Weijing Luan;Shuai Wang;Shanshan Cui;M. Cheng;Yang Liu
用小分子化合物激活p53功能用于结肠癌治疗是高度期望的。三萜皂苷具有良好的选择性和安全性。然而，三萜皂苷作为癌症化疗药物的应用主要受到中等抗癌效力和缺乏作用机制的阻碍。本研究合成了一系列合欢苷A衍生物，并对其体外和体内抗肿瘤活性进行了评价。化合物D13对HCT 116细胞具有较强的抑制活性，IC 50值为5.19 μM。更重要的是，化合物D13具有良好的选择性，并且对MDR癌细胞有效。此外，化合物D13作为p53激活剂可通过线粒体途径诱导细胞凋亡和铁凋亡。此外，化合物D13在体内正常器官中显著抑制肿瘤发生而不诱导毒性。总的来说，这项研究提供了一个临床相关的论点，考虑三萜皂苷衍生物D13作为潜在的癌症治疗候选药物，具有增强的活性，可接受的安全性和新的作用机制。据我们所知，该化合物是第一个可以作为p53激活剂诱导细胞凋亡和铁凋亡的候选药物。
It is highly desirable to activation p53 function with small-molecule compounds for colon cancer therapy. Triterpene saponin has been characterized with the favorable selectivity and safety profiles. However, the application of triterpene saponin as cancer chemotherapy drugs was hampered primarily by moderate anticancer potency and the lack the mechanism of action. In this study, we synthesized a series of Albiziabioside A derivatives and evaluated the antitumor activity bothin vitroandin vivo. CompoundsD13possessed strong inhibitory activity against HCT116 cells with IC50values of 5.19 μM. More importantly, compoundD13had a favorable selectivity and was efficacious against MDR cancer cells. Moreover, compoundD13could induce apoptosis and ferroptosis through the mitochondrial pathway as a p53 activator. In addition, compoundD13significantly suppressed tumorigenesis without inducing toxicity in normal organsin vivo. Collectively, this study provides a clinically relevant argument for considering triterpene saponin derivativesD13as potential cancer therapeutic candidates with enhanced activity, acceptable safety and novel mechanisms of action. To the best of our knowledge, this compound is the first drug candidate which can induce apoptosis and ferroptosis as a p53 activator.