21:T454,Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase (TrxR) inhibition, which disturbs the redox balance of cancer cells.However, in this model, the role of the ligand(s) coordinated to gold is often overlooked.In this work, we present a series of tetrapyridyl Au(III) complexes that exhibit thiol-induced release of a Au(I) ion and a tetrapyridyl ligand.The formation of a free Au(I) center is responsible for the expected TrxR inhibition.Additionally, the released ligand, which was visible in cells due to its intense blue fluorescence, showed excellent binding properties to the hERG potassium channel.Moreover, these ligands ended up in the lysosomes, resulting in significant lysosome damage.Altogether, the Au(III) complexes presented in this work showed broad-spectrum anticancer properties, both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(I) center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.22:T493,Photoactivated chemotherapy agents form a new branch of physically targeted anticancer agents with potentially lower systemic side effects for patients. On the other hand, limited information exists on the intracellular interactions between the photoreleased metal cage and the photoreleased anticancer inhibitor. In this work, we report a new biological study of the known photoactivated compound Ru-STF31 in the glioblastoma cancer cell line, U87MG. Ru-STF31 targets nicotinamide phosphoribosyltransferase (NAMPT), an enzyme overexpressed in U87MG. Ru-STF31 is activated by red light irradiation and releases two photoproducts: the ruthenium cage and the cytotoxic inhibitor STF31. This study shows that Ru-STF31 can significantly decrease intracellular NAD⁺ levels in both normoxic (21% O₂) and hypoxic (1% O₂) U87MG cells. Strikingly, NAD⁺ depletion by light activation of Ru-STF31 in hypoxic U87MG cells could not be rescued by the addition of extracellular NAD⁺. Our data suggest an oxygen-dependent active role of the ruthenium photocage released by light activation.

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