Oxygen-dependent interactions between the ruthenium cage and the photoreleased inhibitor in NAMPT-targeted photoactivated chemotherapy

Photoactivated chemotherapy agents show a promising ability to kill cancer cells under the action of light, including those in chronic hypoxic conditions. Those compounds form a new branch of physically targeted anticancer agents with potentially lower systemic side effects for patients. On the other hand, very few information exists on the intracellular interactions between the photoreleased ruthenium cage and the photoreleased antitcancer inhibitor. In this work, we report a biological study of the photoactivated chemotherapy compound Ru-STF31 in the glioblastoma cancer cell line U87MG. Ru-STF31 targets nicotinamide phosphoribosyltransferase (NAMPT), an enzyme overexpressed in glioblastoma. Ru-STF31 is activated by red-light irradiation, which breaks a bond between the ruthenium-based caging group and the NAMPT inhibitor STF31, thereby releasing two photoproducts: the ruthenium cage and the cytotoxic inhibitor STF31. Ru-STF31 showed significantly higher solubility in water and anticancer efficacy compared with the free inhibitor STF-31. It also significantly decreased intracellular NAD+ levels not only in normoxic (21% O2) but also in hypoxic (1% O2) U87MG cells. Strikingly, NAD+ depletion by red light activation of Ru-STF31 in hypoxic U87MG cells could not be rescued by the addition of extracellular NAD+. Our data suggest an active role of the ruthenium photocage released by light activation.