NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells

作     者：LIU Hui-Ying LI Qing-Ran CHENG Xue-Fang WANG Guang-Ji HAO Hai-Ping 

作者机构：State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Department of Physiology and Pathophysiology School of Basic Medical Sciences Peking University 

出 版 物：《Chinese Journal of Natural Medicines》 (中国天然药物（英文版）)

年 卷 期：2016年第14卷第8期

页      面：582-589页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Nos.81430091,81325025,and 81273586) Jiangsu Provincial Promotion Foundation for the Key Lab of Drug Metabolism and Pharmacokinetics(No.BM2012012) the Natural Science Foundation of Jiangsu Province for Outstanding Youth Scholar(No.BK2012026) 

主　　题：FK866 NQOl-targeting agents Synergy NAD+ SIRT1 

摘      要：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.