Roulston Anne, Shore Gordon C
Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre, and Dept. Biochemistry, McGill University , Montreal, QC, Canada.
Mol Cell Oncol. 2015 Jun 10;3(1):e1052180. doi: 10.1080/23723556.2015.1052180. eCollection 2016 Jan.
Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD(+) metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD(+) in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD(+)/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents.
烟酰胺磷酸核糖转移酶（NAMPT）对哺乳动物细胞中烟酰胺腺嘌呤二核苷酸（NAD(+)）的生物合成至关重要。NAMPT抑制剂是多功能抗癌药物，作用于NAD(+)代谢，以阻断糖酵解、核苷酸生物合成和ATP生成，并间接作为PARP和去乙酰化酶抑制剂发挥作用。NAMPT抑制剂的选择性利用了癌细胞中补充NAD(+)增加的代谢需求。尽管最初使用NAMPT抑制剂的临床研究在达到剂量限制性毒性之前未达到单药治疗水平，但对替代救援途径和可用于选择患者的生物标志物的新认识为扩大治疗窗口并在临床上实现有效剂量提供了新机会。最近的研究还表明，药物联合策略有进一步增加治疗机会的潜力。本综述总结了NAD(+)/NAMPT抑制剂生物学的最新发现，旨在利用这些新知识优化这类有前景的新型药物的临床疗效。
