Oxygen-Dependent Interactions between the Ruthenium Cage and the Photoreleased Inhibitor in NAMPT-Targeted Photoactivated Chemotherapy

Abstract

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 <b>Ru-STF31</b> in the glioblastoma cancer cell line, U87MG. <b>Ru-STF31</b> targets nicotinamide phosphoribosyltransferase (NAMPT), an enzyme overexpressed in U87MG. <b>Ru-STF31</b> is activated by red light irradiation and releases two photoproducts: the ruthenium cage and the cytotoxic inhibitor <b>STF31</b>. This study shows that <b>Ru-STF31</b> can significantly decrease intracellular NAD⁺ levels in both normoxic (21% O₂) and hypoxic (1% O₂) U87MG cells. Strikingly, NAD⁺ depletion by light activation of <b>Ru-STF31</b> 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.