Yang Shu-Ting, Fan Jin-Bao, Liu Ting-Ting, Ning Shuai, Xu Jia-Hao, Zhou Ying-Jun, Deng Xu
Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan 410013, China.
Hunan Key laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, Hunan 410013, China.
J Med Chem. 2022 Jul 19. doi: 10.1021/acs.jmedchem.2c00275.
Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome-lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy.
自噬抑制已被广泛视为一种有前景的抗癌治疗策略。然而，鲜有有效的特异性自噬抑制剂被报道。在此，我们描述了独脚金内酯（SLs）新型类似物的设计、合成及生物学特性，独脚金内酯是一类新出现的植物激素，用于对抗结直肠癌。其中，一种对映体纯的类似物对结直肠癌细胞具有强效且选择性的细胞毒性，但对正常人类结肠黏膜上皮细胞无此作用，平板克隆形成试验进一步证实了这一点。此外，它在HCT116异种移植小鼠模型中显著抑制肿瘤生长且毒性较低。从机制上讲，它与细胞凋亡的选择性诱导和细胞周期阻滞有关。值得注意的是，通过在HCT116细胞中选择性增加自噬通量同时阻断自噬体 - 溶酶体融合，它起到了强效自噬/线粒体自噬抑制剂的作用。本研究以立体定向的SLs作为具有高癌细胞特异性的新型自噬抑制剂为特色，为结直肠癌治疗开辟了一条新途径。
