Tedeschi Philip M, Lin HongXia, Gounder Murugesan, Kerrigan John E, Abali Emine Ercikan, Scotto Kathleen, Bertino Joseph R
Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey
Mol Pharmacol. 2015 Oct;88(4):720-7. doi: 10.1124/mol.114.096727. Epub 2015 Jul 28.
NAD(+) kinase (NADK) is the only known cytosolic enzyme that converts NAD(+) to NADP(+), which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further.
NAD(+)激酶（NADK）是唯一已知的可将NAD(+)转化为NADP(+)的胞质酶，NADP(+)随后被还原为NADPH。癌细胞对NADPH的需求增加，因为增殖细胞中高水平的核苷酸、蛋白质和脂肪酸合成以及中和高水平的活性氧（ROS）都需要还原当量。我们确定抑制NADK活性单独以及与已知可诱导ROS的化疗药物联合使用是否是一种有效的抗癌策略。使用小发夹RNA或硫代烟酰胺在体外和体内抑制NADK均能抑制增殖。硫代烟酰胺增强了几种化疗药物产生的ROS并产生协同细胞杀伤作用。单独使用NADK抑制剂或与增加ROS介导应激的药物联合使用可能代表一种有效的抗肿瘤联合方案，应进一步探索。
