ENHANCED APOPTOSIS BY TARGETING PROTEIN REDOX STATUS

通过靶向蛋白质氧化还原状态来增强细胞凋亡

• 批准号: 7048278
• 负责人: MOHAN NATARAJAN
• 金额: $ 18.79万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-12 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048278
• 关键词: JUN kinase; NAD(P)H oxidoreductase; adduct; aminoacid; antineoplastics; apoptosis; biological signal transduction; cell line; homeostasis; hypoxia inducible factor 1; neoplasm /cancer pharmacology; oxidation reduction reaction; prostate neoplasms; protein binding; protein structure function; serine threonine protein kinase; sesquiterpenes; thioredoxin

DESCRIPTION (provided by applicant): The novel anticancer drugs irofulven and oxaliplatin are consistent and potent apoptosis inducers in tumor cells. Irofulven and oxaliplatin bind to cellular DNA as well as to protein sulfhydryls. While both DNA adducts and protein adducts are important apoptotic stimuli, the potentially lethal consequences of protein reactivity of irofulven and oxaliplatin remain understudied. The purpose of this proposal is to test the hypothesis that irofulven and oxaliplatin target key redox-controlling proteins and the subsequent distortion of the redox status of cellular proteins enhances apoptosis in cancer cells. Protein redox homeostasis is predominantly controlled by the anti-apoptotic thioredoxin (Trx) system. Trx is recognized as a potential target for therapeutic intervention, as many tumors gain growth advantage by elevating their Trx levels. Tumor cells are constantly under abnormally oxidative conditions and, therefore, may be particularly sensitive to drugs impeding the functions of Trx. Preliminary data implicate the Trx system in the effects of irofulven and oxaliplatin. The first aim is to investigate the binding of irofulven and oxaliplatin to Trx and other key redox regulating proteins in their purified forms and in cancer cells. The second aim is to determine the effects of irofulven and oxaliplatin on the functions of cellular redox proteins and the distortion of the redox status of the cell. Modulation of the global cellular redox balance will be examined in the context of the demonstrated resistance of normal cells to irofulven and oxaliplatin. The third aim is to establish a causative link between the targeting of the Trx system, the global distortion of protein redox status, and the induction of apoptosis by irofulven and oxaliplatin. This will include assessing the roles of redox-dependent ASK1 -mediated and AlF-mediated pathways, as well as Trx-dependent HIF-1 signaling under hypoxic conditions. The focus is on prostate cancer models, which are highly relevant to the clinical properties of these drugs. Successful completion of these aims will define the role of the Trx system as a target for irofulven and oxaliplatin, which could significantly improve the clinical use of these drugs. Ultimately, the outcomes should establish a rationale for combining targeting of redox controlling proteins with other specific anti-cancer drugs to maximize apoptosis in cancer cells that are resistant to DNA damaging agents.

描述（由申请人提供）：新型抗癌药物艾洛芬和奥沙利铂是肿瘤细胞中一致且有效的细胞凋亡诱导剂。 Irofulven 和奥沙利铂与细胞 DNA 以及蛋白质巯基结合。虽然 DNA 加合物和蛋白质加合物都是重要的细胞凋亡刺激物，但艾洛芬和奥沙利铂的蛋白质反应性的潜在致命后果仍未得到充分研究。该提案的目的是检验以下假设：罗氟芬和奥沙利铂靶向关键的氧化还原控制蛋白，随后细胞蛋白氧化还原状态的扭曲会增强癌细胞的凋亡。蛋白质氧化还原稳态主要由抗凋亡硫氧还蛋白（Trx）系统控制。 Trx 被认为是治疗干预的潜在靶点，因为许多肿瘤通过提高 Trx 水平来获得生长优势。肿瘤细胞始终处于异常氧化条件下，因此可能对阻碍 Trx 功能的药物特别敏感。初步数据表明 Trx 系统与 irofulven 和奥沙利铂的作用有关。第一个目标是研究 irofulven 和奥沙利铂与 Trx 和其他关键氧化还原调节蛋白（纯化形式）和癌细胞中的结合。第二个目的是确定罗氟芬和奥沙利铂对细胞氧化还原蛋白功能和细胞氧化还原状态扭曲的影响。将在正常细胞对罗氟芬和奥沙利铂已证实的耐药性的背景下检查整体细胞氧化还原平衡的调节。第三个目标是确定 Trx 系统的靶向、蛋白质氧化还原状态的整体扭曲以及罗氟芬和奥沙利铂诱导细胞凋亡之间的因果关系。这将包括评估氧化还原依赖性 ASK1 介导和 AlF 介导途径的作用，以及缺氧条件下 Trx 依赖性 HIF-1 信号传导的作用。重点是前列腺癌模型，它与这些药物的临床特性高度相关。这些目标的成功完成将确定 Trx 系统作为 irofulven 和奥沙利铂靶点的作用，这可以显着改善这些药物的临床使用。最终，结果应该为将氧化还原控制蛋白的靶向与其他特定抗癌药物相结合建立一个基本原理，以最大限度地提高对 DNA 损伤剂具有抗性的癌细胞的凋亡。