Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites
Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites
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DOI：
10.1016/j.chembiol.2018.01.012
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发表时间：
2018-04-19
影响因子：
8.6
通讯作者：
Chiarugi, Alberto
中科院分区：
文献类型：
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作者：
Buonvicino, Daniela;Mazzola, Francesca;Chiarugi, Alberto
烟酰胺腺嘌呤二核苷酸（NAD）代谢组调控的兴趣正在获得巨大的动力，因为它在不同的人类疾病的治疗潜力。然而，通过烟酰胺磷酸核糖转移酶（NAMPT）抑制剂抑制烟酰胺补救，在肿瘤患者中得到了不确定的结果，因为几种代谢途径绕过了直接会聚在烟酰胺单核苷酸腺苷酸转移酶（NMNATs）上的NAD合成的酶阻滞。不幸的是，NMNAT抑制剂尚未被鉴定。在这里，我们报告的鉴定Vacor作为底物代谢的连续行动NAMPT和NMNAT 2到NAD类似物Vacor腺嘌呤二核苷酸（VAD）。这导致两种酶以及NAD依赖性辅酶A酶的抑制，从而引起NMNAT 2-活性癌细胞前所未有的快速NAD消耗、糖酵解阻断、能量衰竭和坏死性死亡。相反，NMNAT 2表达的缺乏赋予对Vacor的完全抗性。值得注意的是，Vacor在NMNAT 2阳性神经母细胞瘤和黑素瘤异种移植物中促进VAD形成和生长抑制。我们的数据显示了利用整个烟酰胺补救途径进行抗代谢策略的第一个证据。
Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies.