Designing a multitarget In(iii) compound to overcome the resistance of lung cancer cells to cisplatin

Abstract

Designing novel anticancer non-platinum metal agents is fully challenging. Herein, a series of little-known indium (In) 2-acetylpyridine thiosemicarbazone compounds as potential anticancer agents were designed, synthesized, and characterized. The hydrogen atoms at the N-4 position with the alkyl of the In compounds significantly increased cellular uptake and cytotoxicity. In(III) compounds showed significantly higher cytotoxicity toward cisplatin-resistant cell lines than cisplatin. More importantly, C4 greatly inhibited A549DDP tumor growth in a vaccinated mouse model. C4 exerted cytotoxic effects via a multitarget mechanism. First, it activated p53 and blocked the cell cycle at the S phase, which then led to weak expression levels of cyclin and related kinases and upregulation of the expression levels of cyclin-dependent kinase inhibitors. C4 also depolarized the mitochondrial membrane potential and regulated the expression of the Bcl-2 family, which then released cyt-c and activated caspase-3/8/9 to execute apoptotic pathways. Then, it inhibited telomerase through the inhibition of the expression of the c-Myc regulator gene and expression of the human telomerase reverse transcriptase. Furthermore, C4 showed excellent antimetastatic activity.