Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance,Journal of Medicinal Chemistry

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Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-30 , DOI: 10.1021/acs.jmedchem.2c00472
Xinyi Wang _{1,

2} , Zhikun Liu _{1,

2} , Yuanjiang Wang _{1,

2} , Shaohua Gou _{1,

2}

Affiliation

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 15 exerted the most potent cytotoxicity against A549 and A549/CDDP cancer cells. Besides, 15 could suppress cancer cell stemness, superior to BBI608, and overcome cisplatin resistance. Following assays indicated that an enhanced intracellular accumulation of 15 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 15 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.

中文翻译：

具有癌症干细胞抑制作用的铂（IV）前药对肺癌克服耐药性的影响

获得性耐药仍然是非小细胞肺癌治疗的主要障碍，而癌症干细胞（CSCs）通常会导致耐药性的发生。我们在此报告了一系列铂 (IV) 前药，其中含有来自轴向位置的已知 CSCs 抑制剂 BBI608 的 CSCs 抑制物质。其中，复合物15对 A549 和 A549/CDDP 癌细胞的细胞毒性最强。此外，15可以抑制癌细胞干细胞，优于BBI608，克服顺铂耐药。以下测定表明，增强的细胞内积累15在 A549/CDDP 细胞中通过 p53 途径有效触发 DNA 损伤、诱导 ROS 生成、激活线粒体凋亡途径并抑制细胞运动。体内试验表明，15表现出有效的抗肿瘤作用，而不会导致体重减轻。我们的研究提供了一种新颖有效的方法来促进铂类前药的抗肿瘤活性，并通过抑制癌细胞干细胞来克服顺铂耐药性。

更新日期：2022-05-30

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