Nicotinaldehyde, a Novel Precursor of NAD Biosynthesis, Abrogates the Anti-Cancer Activity of an NAD-Lowering Agent in Leukemia

SIMPLE SUMMARY: Cancer cells are reliant on a sufficient amount of nicotinamide adenine nucleotide (NAD) to sustain their altered metabolism and proliferation. Targeting NAD depletion with inhibitors of NAD biosynthesis has therefore emerged as a promising approach for cancer treatment. Growing evidence demonstrates the existence of multiple precursors and alternative pathways for NAD biosynthesis, and that many parameters that include gut microbiota may negatively affect the therapeutic efficacy of NAD lowering agents in cancer treatment. These findings raise the need to depict further the NAD biogenesis in mammalian cells in order to improve the efficacy of NAD targeting anti-cancer treatment. In the present study, we report the identification of nicotinaldehyde as a novel NAD precursor in leukemia cells. Our findings reveal the implication of a novel NAD metabolite in modulating the anti-cancer efficacy of an NAD-lowering agent and suggest potential strategies to enhance its therapeutic effect. ABSTRACT: Targeting NAD depletion in cancer cells has emerged as an attractive therapeutic strategy for cancer treatment, based on the higher reliance of malignant vs. healthy cells on NAD to sustain their aberrant proliferation and altered metabolism. NAD depletion is exquisitely observed when NAMPT, a key enzyme for the biosynthesis of NAD, is inhibited. Growing evidence suggests that alternative NAD sources present in a tumor environment can bypass NAMPT and render its inhibition ineffective. Here, we report the identification of nicotinaldehyde as a novel precursor that can be used for NAD biosynthesis by human leukemia cells. Nicotinaldehyde supplementation replenishes the intracellular NAD level in leukemia cells treated with NAMPT inhibitor APO866 and prevents APO866-induced oxidative stress, mitochondrial dysfunction and ATP depletion. We show here that NAD biosynthesis from nicotinaldehyde depends on NAPRT and occurs via the Preiss–Handler pathway. The availability of nicotinaldehyde in a tumor environment fully blunts the antitumor activity of APO866 in vitro and in vivo. This is the first study to report the role of nicotinaldehyde in the NAD-targeted anti-cancer treatment, highlighting the importance of the tumor metabolic environment in modulating the efficacy of NAD-lowering cancer therapy.