Advances in NAD-Lowering Agents for Cancer Treatment

Abstract

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the “salvage pathway” of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.

Quantitative Analysis of Daporinad (FK866) and Its In Vitro and In Vivo Metabolite Identification Using Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry

“…This is because cancer metabolism-related agents can potentially enhance the therapeutic effect when combined with conventional chemotherapies [ 6 , 7 ]. Recently, the biochemical pathway of nicotinamide adenine dinucleotide (NAD) has received much attention among these cancer metabolism researches [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. The NAD is a major co-enzyme of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in glycolysis, a major glucose metabolic pathway in cancer cells, and is also involved in tricarboxylic acid (TCA) cycle and oxidative phosphorylation in cancer cells [ 15 , 16 ].…”

NAMPT Inhibition Induces Neuroblastoma Cell Death and Blocks Tumor Growth

“…to date. Many NAMPT inhibitors are currently under investigation, and several are currently being tested in clinical trials (19,28,29). Common side effects reported in these trials thus far include thrombocytopenia, diarrhea, mucositis, anemia, and leukopenia.…”

“…Studies thus far have predominantly investigated NAMPT inhibitors as few NAPRT and Nicotinamide-nucleotide adenylyltransferase (NMNAT) inhibitors have been identified to date. Many NAMPT inhibitors are currently under investigation, and several are currently being tested in clinical trials ( 19 , 28 , 29 ). Common side effects reported in these trials thus far include thrombocytopenia, diarrhea, mucositis, anemia, and leukopenia.…”

Identification of NAPRT Inhibitors with Anti-Cancer Properties by In Silico Drug Discovery

“…Most studies in this field focused on interrupting the NAM salvage pathway by targeting its rate-limiting enzyme, nicotinamide phosphoribosyltransferase (NAMPT). This reflects the fact that potent and highly active (at least in preclinical models) NAMPT inhibitors, such as FK866 and CHS828, were among the first NAD-lowering agents to be reported [ 15 , 16 , 17 ] and the observation that NAMPT is commonly overexpressed in a variety of human cancers [ 17 , 18 ]. Regrettably, despite their efficacy in preclinical models, NAMPT inhibitors showed poor efficacy in clinical trials [ 19 , 20 , 21 , 22 ], indicating that tumor cells exploit surrogate NAD-producing routes, in particular the PH pathway, to circumvent NAMPT blockade [ 23 , 24 ].…”