Pd(II) and Rh(III) Complexes with Isoquinoline Derivatives Induced Mitochondria-Mediated Apoptotic and Autophagic Cell Death in HepG2 Cells

Nonplatinummetal complexes of [Pd(L-1)Cl-2] (C1), [Rh (L-1)Cl-3(DMSO)] (C2), [Pd(L-2)Cl-2] (C3), and [Rh(L-3) Cl-3(DMSO)] (C4) with isoquinoline derivatives have been prepared and characterized. C1-C4 exhibited higher in vitro anticancer activity and lower toxicity than the corresponding ligands and cisplatin against HepG2 cells. The mechanistic studies revealed that C1 arrested the cell cycle at S-phase by regulation of cyclin and cyclin-dependent kinases. C1 was accumulated in mitochondria, which increased the generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER)-stress response through mitochondrial dysfunction. Moreover, C1 stimulated Ca2+ release, activated the caspase cascade, and triggered mitochondria-mediated apoptosis. The in vivo studies of C1 demonstrated higher safety than cisplatin and effective tumor growth inhibition. C1 is a potential anticancer drug candidate.