Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells

Dinuclear complex [Ir2(μ-L1)(η5-Cp*)2Cl2](PF6)2 (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI50 = 1.7–3.0 μM) and outperformed its mononuclear analogue [Ir(η5-Cp*)Cl(L2)]PF6 (2; GI50 > 40.0 μM); Cp* = pentamethylcyclopentadienyl, L1 = 4-chloro-2,6-bis[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl]pyridine, L2 = 5-(pyridin-2-yl)-1,3,4-thiadiazol-2-amine. Compound 1 upregulated the Keap1/Nrf2 oxidative stress-protective pathway in the treated MV4‐11 acute myeloid leukemia cells. In connection with the redox-mediated mode of action of 1, its NADH-oxidizing activity was detected in solution (1H NMR), while NAD+ remained intact (with formate as a hydride source). Surprisingly, only negligible NADH oxidation was detected in the presence of the reduced glutathione and ascorbate. Following the results of in-solution experiments, NAD(H) concentration was assessed in 1-treated MV4‐11 cancer cells. Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD+, resulting in depletion of both NAD+/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action. Dinuclear Ir(III) complex 1 upregulates the Keap1/Nrf2 oxidative stress-protective pathway in cancer cells. In solution, the ability of 1 to oxidize NADH was suppressed by ascorbate, while no interaction with NAD+ was observed. In contrast, a relevant decrease of both NAD(H) coenzymes was observed in the 1-treated cancer cells. [Display omitted] •dinuclear Ir(III) complex 1 exhibited low micromolar activity in human cancer cells.•in-solution NADH conversion is induced by 1 and reduced by ascorbate.•no NAD+ conversion was observed in solution in the presence of 1.•in cells, 1 upregulated the Keap1/Nrf2 pathway protecting against oxidative stress.•a significant decrease of both NAD(H) coenzymes was induced in cells by 1.