Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, 388 Yu-Hang-Tang Rd, Hangzhou, Zhejiang 310058, China.
Eur J Pharmacol. 2012 Jan 15;674(2-3):163-70. doi: 10.1016/j.ejphar.2011.11.017. Epub 2011 Nov 19.
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in the salvaging pathway for the synthesis of nicotinamide adenine dinucleotide (NAD) that is involved in cell metabolism and proliferation. NAMPT is normally absent in astrocyte but highly expressed in glioblastoma, suggesting that it may promote cell survival through synthesizing more NAD. In this report, we evaluated the effect of APO866, a potent inhibitor of NAMPT against C6 glioblastoma. We found that APO866 inhibited the growth of C6 glioblastoma cells with IC(50) in nano-molar range. APO866 depleted intracellular NAD, caused marked inhibition of ERK activation and induced G2/M cell-cycle arrest. The effects by APO866 were abrogated by nicotinamide mononucleotide (NMN), the direct product of NAMPT. Administration of U0126, an ERK1/2 inhibitor, inhibited cell growth but displayed no synergistic effect with APO866. Taken together, our results indicated that APO866 is a potent growth inhibitor against glioblastoma through targeting NAMPT.
烟酰胺磷酸核糖基转移酶（NAMPT）是从头合成烟酰胺腺嘌呤二核苷酸（NAD）补救途径中的关键酶，NAD 参与细胞代谢和增殖。NAMPT 在星形胶质细胞中通常不存在，但在神经胶质瘤中高度表达，提示其可能通过合成更多的 NAD 促进细胞存活。在本报告中，我们评估了 NAMPT 的强效抑制剂 APO866 对 C6 神经胶质瘤的作用。我们发现 APO866 以纳摩尔级的 IC50 抑制 C6 神经胶质瘤细胞的生长。APO866 耗竭细胞内 NAD，显著抑制 ERK 激活，并诱导 G2/M 细胞周期阻滞。NAMPT 的直接产物烟酰胺单核苷酸（NMN）可消除 APO866 的作用。ERK1/2 抑制剂 U0126 的给药抑制细胞生长，但与 APO866 无协同作用。综上所述，我们的结果表明，APO866 通过靶向 NAMPT 是一种有效的神经胶质瘤生长抑制剂。
