Vitamin B3 derivatives support pancreatic cancer cell survival and chemotherapy resistance

Nicotinamide adenine dinucleotide (NAD⁺) is a central metabolic cofactor essential for cell survival and stress response in normal tissues. Its dietary precursors, commonly referred to as vitamin B3 derivatives, including nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), are marketed as nutraceuticals with potential energy-boosting, cardioprotective, and neuroprotective benefits. Consequently, many cancer patients utilize NAD⁺ precursors to alleviate chemotherapy-induced toxicity and promote health. However, the impact of NAD⁺ supplements on intrinsic tumor biology and progression remains controversial and incompletely characterized. In this study, we assessed the impact of common vitamin B3 derivatives, NAM, NR, and NMN, on chemotherapy efficacy in pancreatic ductal adenocarcinoma (PDAC) using both in vitro and in vivo models. Among the compounds tested, NMN exhibited the strongest protective effect on cancer cells, enhancing resistance to oxaliplatin, 5-fluorouracil, and gemcitabine in vitro. Mechanistically, NAD⁺ precursors promoted mitochondrial function, reduced oxidative stress, and suppressed DNA damage and apoptosis in treated cancer cells, all contributing to chemotherapy resistance. In murine models, both immunocompetent and immunodeficient, supplementation with NAM and NMN similarly conferred resistance to standard chemotherapy and supported cancer growth. Our findings highlight a potentially concerning role for NAD⁺-boosting supplements in the context of an active cancer, especially when used in conjunction with chemotherapy. These data underscore the need for careful evaluation of nutraceutical use in cancer patients, particularly those with PDAC, as vitamin B3 derivatives may inadvertently promote tumor cell survival and compromise treatment efficacy.