NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells.
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.
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.
Hui-Ying
HY
Liu
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Qing-Ran
QR
Li
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Xue-Fang
XF
Cheng
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: guangjiwang@hotmail.com.
Guang-Ji
GJ
Wang
State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: hhp_770505@hotmail.com.
Hai-Ping
HP
Hao
D045784:Abietanes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D045784:Abietanes; D016207:Cytokines; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C021751:tanshinone; D009243:NAD; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
FK866; NAD(+); NQO1-targeting agents; SIRT1; Synergy