Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
J Med Chem. 2022 Jun 9;65(11):7933-7945. doi: 10.1021/acs.jmedchem.2c00472. Epub 2022 May 30.
Acquired resistance remains a major barrier for the treatment of non-small cell lung cancer, while cancer stem cells (CSCs) usually lead to the occurrence of drug resistance. We herein report a series of platinum(IV) prodrugs containing CSCs-inhibitory species derived from a known CSCs inhibitor BBI608 in the axial position. Among them, complex exerted the most potent cytotoxicity against A549 and A549/CDDP cancer cells. Besides, could suppress cancer cell stemness, superior to BBI608, and overcome cisplatin resistance. Following assays indicated that an enhanced intracellular accumulation of effectively triggered DNA damage, induced ROS generation, activated mitochondrial apoptosis pathway, and suppressed cell motility via p53 pathway in A549/CDDP cells. In vivo tests indicated that exhibited potent antitumor effects without causing loss in the body weight. Our study provides a novel and efficient approach to promote the antitumor activity of platinum-based prodrugs and overcome cisplatin resistance via inhibiting cancer cell stemness.
获得性耐药仍然是治疗非小细胞肺癌的主要障碍，而癌症干细胞（CSC）通常导致耐药的发生。本文报道了一系列含 CSCs 抑制物的顺铂（IV）前药，这些抑制物来源于已知的 CSCs 抑制剂 BBI608 中的轴向位置。其中，复合物 对 A549 和 A549/CDDP 癌细胞表现出最强的细胞毒性。此外， 能够抑制肿瘤细胞干性，优于 BBI608，并克服顺铂耐药性。后续的实验表明， 能够有效增强细胞内积累，从而有效触发 DNA 损伤，诱导 ROS 生成，激活线粒体凋亡途径，并通过 p53 途径抑制 A549/CDDP 细胞的迁移。体内实验表明， 能够发挥强大的抗肿瘤作用，而不会导致体重下降。本研究为通过抑制肿瘤细胞干性来提高基于铂的前药的抗肿瘤活性和克服顺铂耐药性提供了一种新的有效方法。
