Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy.
Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132 Genova, Italy.
Nutrients. 2021 May 14;13(5):1665. doi: 10.3390/nu13051665.
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.
烟酰胺腺嘌呤二核苷酸 (NAD) 是一种必需的氧化还原辅助因子，但它也可以作为消耗 NAD 的酶的底物，调节细胞事件，如 DNA 修复和基因表达。由于这些过程是支持癌细胞存活和增殖的基础，因此持续产生 NAD 是许多类型肿瘤的标志。通过干扰 NAD 生物合成机制来耗尽肿瘤内 NAD 水平已成为一种有前途的抗癌策略。NAD 可以从色氨酸或烟酸中产生。此外，NAD 产生的“补救途径”，使用 NAD 降解的副产物烟酰胺作为底物，在哺乳动物细胞中也广泛活跃，并且似乎被人类癌症中的一部分子集高度利用。事实上，研究主要集中在抑制后者 NAD 产生途径的关键酶，烟酰胺磷酸核糖转移酶（NAMPT），导致了许多抑制剂的鉴定，包括 FK866 和 CHS-828。不幸的是，这些药物的临床活性证明是有限的，这表明需要改进针对肿瘤中 NAD 产生的方法。在这篇文章中，我们强调了该领域的最新进展，包括迄今为止报道的降低 NAD 化合物的概述以及相关的体外和体内研究。我们还描述了关键的 NAD 产生途径及其在癌细胞中的调节。最后，我们总结了探索优化 NAMPT 抑制剂在癌症中的治疗反应的方法。
