NAD+ Boosting Through NRH Supplementation Enhances Treatment Efficacy in EOC In Vitro

Area of Science:

• Biochemistry and Molecular Biology
• Oncology
• Cellular Metabolism

Background:

• Nicotinamide adenine dinucleotide (NAD+) is a critical cofactor for cellular functions, including metabolism and DNA repair.
• Epithelial ovarian cancer (EOC) is characterized by altered cellular metabolism and impaired DNA repair, impacting NAD+ levels.
• Dihydronicotinamide riboside (NRH), a reduced NAD+ precursor, shows potential for boosting NAD+ levels more effectively than traditional precursors.

Purpose of the Study:

• To investigate the cytotoxic effects of NRH supplementation in EOC cell lines.
• To assess the potential of NRH to enhance the efficacy of standard chemotherapeutic agents in EOC.
• To explore the underlying mechanisms of NRH-induced cytotoxicity and its impact on cellular energy metabolism.

Main Methods:

• Treatment of EOC cell lines (OVCAR8, ES2, SKOV3) with NRH and nicotinic acid (NA).
• Assessment of cellular cytotoxicity and NAD(P)H levels following NRH supplementation.
• Evaluation of NRH's effect on the cytotoxicity of carboplatin, paclitaxel, and olaparib (PARP inhibitor).

Main Results:

• NRH supplementation induced significant cytotoxicity (~40%) in EOC cells, while NA had minimal effect.
• NRH increased intracellular NAD(P)H levels, with varying degrees across cell lines.
• NRH enhanced the cytotoxicity of carboplatin and paclitaxel in OVCAR8 cells, and olaparib in OVCAR8 and SKOV3 cells, impacting mitochondrial respiration.

Conclusions:

• NRH supplementation is a viable strategy to exploit the NAD+ bioenergetic phenotype in EOC, potentially enhancing therapeutic responses.
• NRH demonstrates synergistic cytotoxicity with standard therapies, suggesting a role in overcoming treatment resistance.
• NAD+ metabolomics may serve as a biomarker for guiding EOC treatment decisions involving NRH.