SUPEROXIDE DISMUTASE--A NOVEL TARGET FOR CANCER THERAPY

超氧化物歧化酶——癌症治疗的新靶点

• 批准号: 6626750
• 负责人: Peng Huang
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-23 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626750
• 关键词: anthracyclines; antineoplastics; apoptosis; bleomycin; computer simulation; cytochrome c; doxorubicin; drug interactions; enzyme inhibitors; estradiol; free radical oxygen; free radicals; gene induction /repression; membrane lipids; oxidative stress; pharmacogenetics; pharmacology; radiobiology; superoxide dismutase; tissue /cell culture

DESCRIPTION: Superoxide dismutases (SOD) are a class of essential enzymes responsible for the elimination of the toxic free radical, superoxide (O2-), and thus protect cells from oxidative stress. Inhibition of SOD impairs the ability of cells to cope with free radicals, and may provide a new strategy to kill cancer cells by mechanisms involving free radical O2- induced apoptotic cell death. However, specific SOD inhibitors with anticancer activity are not readily available for testing this new strategy. The applicant recently discovered that certain estrogen derivatives inhibited both the cellular copper/zinc-containing superoxide dismutase (CuZnSOD) and the mitochondrial manganese-containing superoxide dismutatase (MnSOD), and preferentially induced apoptosis in cancer cells but not in normal human lymphocytes. Based on these observations, the applicants propose to test the hypothesis of targeting SOD by the estrogen derivatives as a new strategy for cancer therapy. The objectives of this proposal are to investigate the biological consequences of SOD inhibition, to investigate the mechanisms by which the estrogen derivatives inhibit SOD, and to design new mechanism-based strategies to enhance the anticancer activity of the SOD-targeting compounds. Specifically, new molecular biology techniques and pharmacological/biochemical approaches will be employed to investigate the role of SOD inhibition in causing cell death by the estrogen derivatives, and to examine the free radical-mediated damage to membrane lipids, DNA, and relevant proteins such as cytochrome c. Changes in gene expression profiles associated with the estrogen derivative-induced apoptosis will be analyzed by cDNA micro-array technology. They will also use biochemical approaches to characterize the kinetics of SOD inhibition by estrogen derivatives. Laboratory investigations will be combined with computer-assisted molecular simulation technology to determine the structure-function relationship during SOD inhibition. Furthermore, the possibility of combining the SOD inhibitors with radiation and other agents such as anthracyclines that produce free radicals in cells as new strategies to enhance the anticancer activity will be tested. They anticipate that this research project will further our understanding of the mechanisms of SOD inhibition and its biological consequences, and will provide a basis both for the rational design of more potent/selective SOD inhibitors suitable for cancer therapy, and for the development of new mechanism-based strategies to enhance anticancer activity and selectivity.

说明：超氧化物歧化酶是一类必需的酶。 负责清除有毒的自由基，超氧化物(O2-)， 从而保护细胞免受氧化应激的伤害。抑制超氧化物歧化酶损伤细胞 细胞应对自由基的能力，并可能提供一种新的策略 氧自由基致肿瘤细胞凋亡机制的研究 细胞死亡。然而，具有抗癌活性的特定超氧化物歧化酶抑制剂并不是 随时可用于测试这一新策略。最近的申请者 发现某些雌激素衍生物抑制细胞 铜锌超氧化物歧化酶与线粒体 含锰超氧化物歧化酶(MnSOD)，并优先诱导 癌细胞中的细胞凋亡，而正常人的淋巴细胞中不存在。基于这些 根据观察，申请人建议通过以下方式来检验靶向超氧化物歧化酶的假设 雌激素衍生物作为一种新的癌症治疗策略。目标 这项建议的目的是研究超氧化物歧化酶的生物学后果 抑制，以研究雌激素衍生物的机制 抑制超氧化物歧化酶，并设计新的基于机制的策略来增强 超氧化物歧化酶靶向化合物的抗癌活性。具体来说，新分子 将采用生物技术和药理/生化方法。 超氧化物歧化酶抑制在雌激素致细胞死亡中的作用 并检测自由基对膜的损伤。 脂质、DNA和相关蛋白质，如细胞色素c.基因的变化 雌激素衍生物诱导细胞凋亡相关基因的表达谱 将通过基因芯片技术进行分析。他们还将使用生化 雌激素抑制超氧化物歧化酶动力学的研究进展 衍生品。实验室调查将与计算机辅助相结合 确定结构-功能的分子模拟技术 超氧化物歧化酶抑制过程中的相互关系。此外，组合的可能性 超氧化物歧化酶抑制剂与辐射和其他药物，如蒽环类药物 在细胞中产生自由基作为增强抗癌作用的新策略 将对活动进行测试。他们预计这项研究项目将 进一步了解超氧化物歧化酶的抑制机制及其作用机制 生物后果，并将为合理设计提供依据 更有效/更选择性的适用于癌症治疗的超氧化物歧化酶抑制剂，以及 基于机制的增强抗癌新策略的发展 活性和选择性。