Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
Department of Rheumatology and Immunology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
Inorg Chem. 2024 Mar 18;63(11):5235-5245. doi: 10.1021/acs.inorgchem.4c00321. Epub 2024 Mar 7.
Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. and antimetastatic experiments demonstrated that can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. evaluation indicated that restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.
由于癌细胞的智能生物学系统，癌症治疗面临着严峻的障碍。在此，我们报告了一种三功能试剂，通过下调线粒体导向化疗中标志物 CD133 的表达来减弱癌细胞干性。超过 80%的 可以在线粒体中积累，导致严重的线粒体功能障碍，随后引发自噬和细胞周期停滞，从而杀死顺铂耐药的 A549R 细胞。体内转移和抗转移实验表明， 可以有效抑制转移，下调 MMP-2/MMP-9。RNA 测序分析和 Western blot 表明， 还抑制 GSTP1 的表达，减少细胞内 Pt-GS 加合物，从而使 A549R 细胞对顺铂解毒和再敏感。体内评价表明， 抑制肿瘤生长，副作用极小，生物相容性好。这项工作不仅提供了第一个三功能试剂来减弱癌细胞干性，同时实现抗癌、抗转移和克服金属药物耐药性，还证明了线粒体定向策略在癌症治疗中的有效性。
