Redox Signaling and Cancer Drug Action

氧化还原信号传导和癌症药物作用

• 批准号: 8637738
• 负责人: GARTH POWIS
• 金额: $ 32.65万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637738
• 关键词: Angiogenic Factor; Antineoplastic Agents; Apoptotic; Cancer Cell Growth; Cell Death; Cell Survival; Cell physiology; Cells; Clinical Trials; Colorectal Cancer; Correlative Study; Cysteine; Development; Drosophila genus; Drug Targeting; Drug effect disorder; Endoplasmic Reticulum; Family member; Fibroblast Growth Factor 2; Genes; Genetic; Grant; Growth; Growth Factor; Heat shock proteins; Human; In Vitro; Lysophospholipids; Malignant Neoplasms; Mediating; Modification; Molecular Target; Oxidation-Reduction; Pathway interactions; Patients; Phase II Clinical Trials; Phosphorylation; Polyamines; Post-Translational Protein Processing; Proteins; Regulation; Research Design; Role; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Stress; Sulfhydryl Compounds; Testing; Thioredoxin; Translations; Vascular Endothelial Growth Factors; Work; base; cancer cell; drug development; drug discovery; experience; fly; in vivo; inhibitor/antagonist; lysophosphatidic acid; novel; oxidation; pleurotin; response; stress protein; thioredoxin reductase; tumor; tumor growth

ABSTRACT Thioredoxin family members involved in cellular protein signaling networks provide an important mechanism regulating many aspects of cell function including proliferation and cell survival. Redox signaling involves a protein post translational modification second in importance only to protein phosphorylation. Unlike protein phosphorylation little is known of redox signaling networks in the cell or how they are altered in cancer. The increased expression of one redox signaling protein in particular thioredoxin-1 (Trx-1) has been associated with aggressive tumor growth, decreased apoptotic cell death and decreased patient survival. The hypothesis upon which our studies are based is that redox signaling through thioredoxin family members is an important signaling mechanism that is deranged in cancer and that understanding redox signaling networks in the cancer cell will allow the identification of novel molecular targets for cancer drug discovery and development, and new strategies to treat cancer. We have used Drosophila genetics together with functional genetic siRNA studies in human cancer cells to identify new redox signaling pathways which we will investigate in human cancer cells. We will also investigate the redox regulation of the unfolded protein response (UPR) which is important for maintaining the synthesis of cell survival proteins during stress, including many angiogenic factors important in cancer. We will conduct in vivo antitumor and mechanistic studies of an inhibitor of Trx-1 in colorectal cancer and of a new antitumor inhibitor of thioredoxin reductase we have developed. The overall objective of our studies is to use redox signaling pathways in cancer to identify new molecular targets for cancer drug discovery and development, and to provide new strategies to treat cancer. The work builds upon our past studies of Trx-1 as a cancer drug target which has led to the development of one cancer drug in clinical trial, and seeks to identify new pathways of redox signaling by thioredoxin family members for the identification of molecular targets for cancer drug discovery.

摘要 硫氧还蛋白家族成员参与细胞蛋白信号网络提供了一个重要的机制 调节细胞功能的许多方面，包括增殖和细胞存活。氧化还原信号传导涉及 蛋白质翻译后修饰的重要性仅次于蛋白质磷酸化。不像蛋白质 磷酸化对细胞中氧化还原信号网络或它们在癌症中如何改变知之甚少。的 一种氧化还原信号传导蛋白，特别是硫氧还蛋白-1（Trx-1）的表达增加与 具有侵袭性肿瘤生长、减少的凋亡性细胞死亡和减少的患者存活。的假设 我们的研究所基于的是，通过硫氧还蛋白家族成员的氧化还原信号传导是重要的 癌症中紊乱的信号机制，以及理解癌症中的氧化还原信号网络， 细胞将允许识别癌症药物发现和开发的新分子靶点， 治疗癌症的策略。我们使用果蝇遗传学和功能性遗传siRNA研究， 人类癌细胞，以确定新的氧化还原信号通路，我们将在人类癌细胞中进行研究。 我们还将研究未折叠蛋白反应（UPR）的氧化还原调节，这对于 在应激过程中维持细胞存活蛋白的合成，包括许多在 癌我们将在大肠癌中进行Trx-1抑制剂的体内抗肿瘤和机制研究 以及我们开发的一种新的抗肿瘤硫氧还蛋白还原酶抑制剂。我们的总体目标是 研究是利用癌症中的氧化还原信号通路来确定癌症药物的新分子靶点 发现和发展，并提供治疗癌症的新策略。这项工作建立在我们的过去之上 Trx-1作为癌症药物靶标的研究已经导致在临床试验中开发出一种癌症药物， 并寻求通过硫氧还蛋白家族成员鉴定氧化还原信号传导的新途径， 癌症药物发现的分子靶点。

项目成果

The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging.

• 发表时间: 2005-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: B. Jordan;M. Runquist;N. Raghunand;R. Gillies;W. Tate;G. Powis;A. Baker

Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase.

• DOI: 10.1007/s00280-010-1500-0
• 发表时间: 2011-08
• 期刊: CANCER CHEMOTHERAPY AND PHARMACOLOGY
• 影响因子: 3
• 作者: Kim, Yon Hui;Coon, Amy;Baker, Amanda F.;Powis, Garth
• 通讯作者: Powis, Garth

In Vivo Therapeutic Silencing of Hypoxia-Inducible Factor 1 Alpha (HIF-1α) Using Single-Walled Carbon Nanotubes Noncovalently Coated with siRNA.

• DOI: 10.1007/s12274-009-9026-7
• 发表时间: 2009-04-17
• 期刊: NANO RESEARCH
• 影响因子: 9.9
• 作者: Bartholomeusz, Geoffrey;Cherukuri, Paul;Kingston, John;Cognet, Laurent;Lemos, Robert, Jr.;Leeuw, Tonya K.;Gumbiner-Russo, Laura;Weisman, R. Bruce;Powis, Garth
• 通讯作者: Powis, Garth

Superoxide dismutase is regulated by LAMMER kinase in Drosophila and human cells.

• DOI: 10.1016/j.freeradbiomed.2008.12.012
• 发表时间: 2009-03-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: James, Brian P.;Staatz, William D.;Wilkinson, Sarah T.;Meuillet, Emmanuelle;Powis, Garth
• 通讯作者: Powis, Garth

Increased skin carcinogenesis in a keratinocyte directed thioredoxin-1 transgenic mouse.

角化细胞定向硫氧还蛋白-1 转基因小鼠皮肤癌发生增加。

• DOI: 10.1093/carcin/bgh195
• 发表时间: 2004
• 期刊: Carcinogenesis.
• 作者: Mustacich,Debbie;Wagner,Amary;Williams,Ryan;Bair,Warner;Barbercheck,Loretta;Stratton,StevenP;Bhattacharyya,AchyutK;Powis,Garth
• 通讯作者: Powis,Garth