New copper complexes inducing bimodal death through apoptosis and autophagy in A549 cancer cells

Abstract

Two copper complexes, Cu1 (CuL¹Cl₂, L¹ = 2-(6,7-dimethoxyisoquinolin-1-yl) aniline) and Cu2 (CuL²Cl₂, L² = 2-(6-methoxyisoquinolin-1-yl) aniline), were synthesized and characterized. These complexes exhibited high cytotoxic activity toward different cancer cell lines, including the A549 lung cancer cell line, and low cytotoxicity toward normal human cells. Mechanistic studies have shown that these complexes induce bimodal death of cancer cells through apoptosis and autophagy, including the activation of apoptotic and autophagic cell signaling pathways. In addition, Cu1 and Cu2 interacted with calf thymus DNA (ct-DNA) via an intercalative binding mode. The different biological behaviors of these copper complexes could be attributed to the presence of electron-donating methoxy groups on the ligands. Cu1 and Cu2 effectively inhibited tumor growth in a xenografted mouse model bearing A549 cells but exhibited lower in vivo toxicity than cisplatin. Thus, Cu1 and Cu2 can be developed as potential anticancer agents.

Keywords: Anticancer activity; Apoptosis; Autophagy; Cell cycle; Copper agent; Isoquinoline.