Roy Krishnendu K, Lu Jiamo, Doroshow James H
Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Antioxidants (Basel). 2021 Nov 3;10(11):1757. doi: 10.3390/antiox10111757.
Recent studies suggest that of the molecules postulated to function as inhibitors of the NADPH oxidase family of enzymes iodonium analogs known to broadly interfere with flavin dehydrogenase function demonstrate mechanistic validity as NADPH oxidase poisons. In recent work, we have produced a series of novel iodonium compounds as putative inhibitors of these oxidases. To evaluate the potential utility of two novel molecules with favorable chemical properties, NSC 740104 and NSC 751140, we compared effects of these compounds to the two standard inhibitors of this class, diphenyleneiodonium and di-2-thienyliodonium, with respect to antiproliferative, cell cycle, and gene expression effects in human colon cancer cells that require the function of NADPH oxidase 1. Both new agents blocked NADPH oxidase-related reactive oxygen production, inhibited tumor cell proliferation, produced a G1/S block in cell cycle progression, and inhibited NADPH oxidase 1 expression at the mRNA and protein levels at low nM concentrations in a fashion similar to or better than the parent molecules. These studies suggest that NSC 740104 and NSC 751140 should be developed further as mechanistic tools to better understand the role of NADPH oxidase inhibition as an approach to the development of novel therapeutic agents for colon cancer.
近期研究表明，在被假定为烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶家族酶抑制剂的分子中，已知能广泛干扰黄素脱氢酶功能的碘鎓类似物，作为NADPH氧化酶毒物具有机制有效性。在最近的工作中，我们制备了一系列新型碘鎓化合物作为这些氧化酶的假定抑制剂。为评估具有良好化学性质的两种新型分子NSC 740104和NSC 751140的潜在效用，我们将这些化合物与该类别的两种标准抑制剂二亚苯基碘鎓和二 - 2 - 噻吩基碘鎓进行比较，观察它们对需要NADPH氧化酶1功能的人结肠癌细胞的抗增殖、细胞周期和基因表达的影响。两种新试剂均阻断了与NADPH氧化酶相关的活性氧生成，抑制肿瘤细胞增殖，在细胞周期进程中产生G1/S期阻滞，并在低纳摩尔浓度下以类似于或优于母体分子的方式抑制NADPH氧化酶1在mRNA和蛋白质水平的表达。这些研究表明，NSC 740104和NSC 751140应进一步开发为机制工具，以更好地理解抑制NADPH氧化酶作为开发结肠癌新型治疗药物方法的作用。
