NADPH Oxidases as Novel Targets for Cancer Therapy

NADPH 氧化酶作为癌症治疗的新靶点

• 批准号: 10926055
• 负责人: James Doroshow
• 金额: $ 116.6万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926055
• 关键词: Angiogenesis Inhibitors; Cancer Cell Growth; Cell Cycle; Cell Proliferation; Colon Carcinoma; Colorectal Cancer; Down-Regulation; Drug Targeting; EGF gene; Epithelium; Flavoproteins; Future; G1/S Transition; Genes; Goals; Growth; Growth Factor; HT29 Cells; Human; Induction of Apoptosis; Inflammatory; Knock-out; Laboratories; Ligand Binding; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Membrane; Modification; NADP; NADPH Oxidase; NADPH Oxidase 1; Oxidants; Oxidases; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Play; Production; Protein Isoforms; Protein Kinase; Protein Tyrosine Phosphatase; Proteins; Reactive Inhibition; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Regulation; Role; Series; Serine; Signal Transduction; Signal Transduction Pathway; Superoxides; Therapeutic; Therapeutic Agents; Threonine; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; angiogenesis; cell growth; colon cancer cell line; cytokine; in vivo; inhibitor; interest; member; neoplastic cell; novel; novel therapeutic intervention; receptor; small hairpin RNA; targeted cancer therapy

Epithelial NADPH oxidases are flavoproteins that catalyze the NADPH-dependent reduction of oxygen to superoxide following binding of ligands for receptor tyrosine kinases (including EGF, PDGF, VEGF). Current evidence suggests that NADPH-dependent reactive oxygen species play a critical role in growth factor-mediated signal transduction, and that the NADPH oxidase 1 isoform is abundantly expressed in human colon cancers. Because inhibition of constitutive oxidant production and cell growth of human colon cancer cell lines, as well as induction of apoptosis and blockade of the G1/S transition and induction of p27, occurred over the same concentration range for a series of iodonium-based flavoprotein inhibitors, Dr. Doroshows studies suggest that the therapeutic potential of iodonium NADPH oxidase inhibitors may be related to modification of redox-related signal transduction pathways essential for colorectal cancer cell growth. Iodonium derivatives have also been found to be active in two human colon cancer xenograft models. In future studies, Dr. Doroshow plans to develop additional, novel members of the iodonium drug class as potential therapeutic agents. Dr. Doroshow has also employed stable shRNA constructs developed in his laboratory (that are capable of downregulating NADPH oxidase 1 expression by >80%) to specifically investigate the role of this protein in colorectal cancer cell proliferation. These recent studies demonstrate that downregulation of NADPH Oxidase 1 leads to a significant decrease in reactive oxygen production in HT-29 cells, a G1 cell cycle block, down regulation of a large number of antiangiogenic genes, and inhibition of reactive oxygen-mediated signaling through several receptor protein kinases. In addition, we have found that the activity of several serine threonine and tyrosine phosphatases are increased when NADPH oxidase is knocked out. In vivo, downregulation of NADPH oxidase 1 dramatically decreases the growth of HT-29 xenografts, in part due to diminished angiogenesis. We have also found that pro-inflammatory cytokines involved in the pathogenesis of colon cancer strongly upregulate NADPH Oxidase 1. These studies strongly suggest that NADPH oxidase 1 is an important potential drug target in colon cancer.

上皮细胞NADPH氧化酶是黄素蛋白，其在与受体酪氨酸激酶（包括EGF、PDGF、VEGF）的配体结合后催化NADPH依赖性的氧还原成超氧化物。目前的证据表明，NADPH依赖性活性氧在生长因子介导的信号转导中起关键作用，并且NADPH氧化酶1亚型在人类结肠癌中大量表达。由于对人结肠癌细胞系的组成性氧化剂产生和细胞生长的抑制，以及对细胞凋亡的诱导和对G1/S转换的阻断以及对p27的诱导，在一系列碘鎓基黄素蛋白抑制剂的相同浓度范围内发生，Doroshows博士的研究表明，碘鎓 NADPH氧化酶抑制剂的治疗潜力可能与氧化还原修饰有关。结直肠癌细胞生长所必需的相关信号转导途径。还发现碘鎓衍生物在两种人结肠癌异种移植模型中具有活性。在未来的研究中，Doroshow博士计划开发碘鎓类药物的其他新成员作为潜在的治疗药物。Doroshow博士还使用了他实验室开发的稳定的shRNA构建体（能够下调NADPH氧化酶1表达80%）来专门研究这种蛋白质在结直肠癌细胞增殖中的作用。这些最近的研究表明，NADPH氧化酶1的下调导致HT-29细胞中活性氧产生的显著减少，G1细胞周期阻滞，大量抗血管生成基因的下调，以及通过几种受体蛋白激酶抑制活性氧介导的信号传导。此外，我们还发现，当敲除NADPH氧化酶时，几种丝氨酸、苏氨酸和酪氨酸磷酸酶的活性会增加。在体内，NADPH氧化酶1的下调显著降低HT-29异种移植物的生长，部分原因是血管生成减少。我们还发现，参与结肠癌发病机制的促炎细胞因子强烈上调NADPH氧化酶1。这些研究强烈表明NADPH氧化酶1是结肠癌中重要的潜在药物靶点。

项目成果

Effects of Iodonium Analogs on Nadph Oxidase 1 in Human Colon Cancer Cells.

• DOI: 10.3390/antiox10111757
• 发表时间: 2021-11-03
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Roy KK;Lu J;Doroshow JH
• 通讯作者: Doroshow JH

Effect of Anticancer Quinones on Reactive Oxygen Production by Adult Rat Heart Myocytes.

• DOI: 10.1155/2020/8877100
• 发表时间: 2020
• 期刊: Oxidative medicine and cellular longevity
• 作者: Doroshow JH

Decoding NADPH oxidase 4 expression in human tumors.

• DOI: 10.1016/j.redox.2017.05.016
• 发表时间: 2017-10
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Meitzler JL;Makhlouf HR;Antony S;Wu Y;Butcher D;Jiang G;Juhasz A;Lu J;Dahan I;Jansen-Dürr P;Pircher H;Shah AM;Roy K;Doroshow JH
• 通讯作者: Doroshow JH

Expression of NADPH oxidase homologues and accessory genes in human cancer cell lines, tumours and adjacent normal tissues.

NADPH 氧化酶同源物和辅助基因在人类癌细胞系、肿瘤和邻近正常组织中的表达。

• DOI: 10.1080/10715760902918683
• 发表时间: 2009-06
• 期刊: Free radical research
• 影响因子: 3.3
• 作者: Juhasz A;Ge Y;Markel S;Chiu A;Matsumoto L;van Balgooy J;Roy K;Doroshow JH
• 通讯作者: Doroshow JH

Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases.

NADPH 氧化酶的有效选择性碘鎓类抑制剂的表征。

• DOI: 10.1016/j.bcp.2017.07.007
• 发表时间: 2017-11-01
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Lu J;Risbood P;Kane CT Jr;Hossain MT;Anderson L;Hill K;Monks A;Wu Y;Antony S;Juhasz A;Liu H;Jiang G;Harris E;Roy K;Meitzler JL;Konaté M;Doroshow JH
• 通讯作者: Doroshow JH