Liu Hui-Ying, Li Qing-Ran, Cheng Xue-Fang, Wang Guang-Ji, Hao Hai-Ping
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Chin J Nat Med. 2016 Aug;14(8):582-9. doi: 10.1016/S1875-5364(16)30068-1.
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.
烟酰胺磷酸核糖转移酶（NAMPT）催化将烟酰胺转化为NAD⁺的第一步限速反应，NAD⁺对于多种参与各种细胞过程的酶和调节蛋白至关重要，包括调节几种肿瘤抑制因子（如p53和FOXO）的去乙酰化酶SIRT1。在此我们报告，NQO1底物丹参酮IIA（TSA）和β-拉帕醌（β-lap）可迅速耗尽NAD⁺池，但适应性地显著上调NAMPT。FK866以无毒剂量抑制NAMPT可显著增强NQO1靶向剂诱导的凋亡细胞死亡。与单独使用TSA或β-lap处理相比，联合FK866处理可导致更显著地耗尽NAD⁺、抑制SIRT1活性，从而增加乙酰化FOXO1的积累并激活凋亡途径。总之，本研究结果支持NAMPT抑制可与NQO1激活协同作用诱导凋亡细胞死亡，从而为开发联合治疗药物对抗非小细胞肺癌提供了新的理论依据。
