Dual-targeting antitumor conjugates derived from platinum(IV) prodrugs and microtubule inhibitor CA-4 significantly exhibited potent ability to overcome cisplatin resistance

[Display omitted] •Complex 9 significantly induced cell apoptosis and arrested the cell cycle G2/M stage.•Complex 9 dramatically disrupted the microtubule organization.•Complex 9 exhibited certain ability to overcome cisplatin resistance.•Complex 9 showed higher cytotoxicity and lower toxicity than cisplatin.•Complex 9 might induce cell apoptosis through mitochondrion pathway. Here we report that three platinum(IV) prodrugs containing a tubulin inhibitor CA-4, as dual-targeting platinum(IV) prodrug, were synthesized and evaluated for antitumor activity using MTT assay. Among them, complex 9 exhibited the most potent antitumor activity against the tested cancer lines including cisplatin resistance cancer cells, and simultaneously displayed lower toxicity compared to cisplatin, respectively. Moreover, complex 9, in which was conjugated to an inhibitor of tubulin at one axial position of platinum(IV) complex, could effectively enter the cancer cells, and significantly induce cell apoptosis and arrest the cell cycle in A549 cells at G2/M stage, and dramatically disrupt the microtubule organization. In addition, mechanism studies suggested that complex 9 significantly induced reactive oxygen species (ROS) generation and decreased mitochondrial trans-membrane potential (MMP) in A549 cells, and effectively induced activation of caspases triggering apoptotic signaling through mitochondrial dependent apoptosis pathways.