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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 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.

SUBMITTER: Abyar S

PROVIDER: S-EPMC11247496 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Abyar Selda S Huang Luojiao L Husiev Yurii Y Bretin Ludovic L Chau Bobby B Ramu Vadde V Wildeman Jacob Hendricus JH Belfor Kimberley K Wijaya Lukas S LS van der Noord Vera E VE Harms Amy C AC Siegler Maxime A MA Le Dévédec Sylvia E SE Bonnet Sylvestre S

Journal of medicinal chemistry 20240626 13

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 phos ...[more]

PMID: 38924492

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Project description:Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.

Dataset Information

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

Publications

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

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