Bioinspired Rational Design of a Light-Regulated Mimic of NADH Oxidase: Photoactivated Iridium–Phenanthroline Complex Induces NADH Oxidation, ROS Generation, p38 MAPK Activation, and AIF-Dependent Apoptosis in A549 Lung Cancer Cells

In this study, [Ir(CO6)2(phen)]Cl (Ir-Phe), where CO6 = Coumarin 6, phen = 1, 10-phenanthroline, was developed as a light-regulated mimic of NADH oxidase (NOX) for phototoxic activities in lung cancer (A549) cells. The cell-free studies established that Ir-Phe, upon exposure to green light (525 nm, 13.95 mW/cm2), catalyzed the photo-oxidation of NADH with a turnover frequency of 621.4 ± 32.6 h-1 in an aqueous solution. Ir-Phe demonstrated potent cytotoxicity (IC50 = 4.54 µM) under dark conditions via reductive stress, decreasing basal ROS and concurrently increasing GSH in A549 cancer cells. The cytotoxicity of Ir-Phe was greatly enhanced upon photoactivation, yielding an IC50 of 50 nM and a photocytotoxicity index (dark IC50/light IC50) of ∼85, respectively. Interestingly, under light, Ir-Phe exhibited a completely different mechanism from that observed in the dark. Under light, Ir-Phe combined type I and II photocatalytic anticancer mechanisms (reactive oxygen species generation and in-cell NADH oxidation), ultimately leading to activation of the p38MAPK stress signaling pathway, followed by cell death through caspase-independent AIF-mediated apoptosis. Overall, this is the first example of an anticancer Ir(III) complex that can switch its anticancer pathway depending on the treatment demand (in the dark or in light).