Mitochondrial defects and Cancer Therapeutics

线粒体缺陷和癌症治疗

• 批准号: 7394515
• 负责人: Peng Huang
• 金额: $ 29.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-07 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394515
• 关键词: Alteration in Respiration; Antineoplastic Agents; Apoptosis; BAD gene; Bad protein; Biochemical; Biological Models; Cell Death; Cell Survival; Cells; DNA Damage; DNA Repair; Defect; Dependency; Disease; Energy Metabolism; Energy Supply; Frequencies; Generations; Genetic; Glycolysis; Human; Injury; Laboratories; Lead; Malignant Neoplasms; Mediating; Metabolic; Methodology; Methods; Mitochondria; Mitochondrial DNA; Molecular; Molecular Biology; Mutate; Mutation; Normal Cell; Oncogenic; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Play; Production; Publications; Reactive Oxygen Species; Research; Respiration; Respiratory Chain; Role; Science; Signal Transduction; Stress; Superoxides; System; Testing; Therapeutic; Warburg Effect; anticancer activity; base; cancer cell; clinically relevant; design; drug sensitivity; inhibitor/antagonist; innovation; insight; killings; mitochondrial DNA mutation; mutant; novel; novel strategies; novel therapeutics; pro-apoptotic protein; response

DESCRIPTION (provided by applicant): It has long been recognized that cancer cells and normal cells have different energy metabolic patterns. One longstanding and prominent observation is that cancer cells show increased glycolysis even in the presence of the adequate oxygen supply, a phenomenon known as Warburg effect. Although the increased dependency on glycolysis for ATP supply has been observed consistently in a wide spectrum of human cancers, the biochemical and molecular mechanisms responsible for this metabolic alteration and its therapeutic implications remain to be elucidated. Recent studies by several groups, including our laboratory, showed that mitochondrial DNA (mtDNA) is frequently mutated in human cancer cells, associated with alterations in drug sensitivity. Because mitochondria play essential roles both in ATP production and apoptosis, we hypothesize that mitochondrial DNA mutations and the consequent malfunction of the mitochondrial respiratory chain lead to a decrease in ATP production through oxidative phosphorylation, forcing the malignant cells to increased glycolysis to maintain energy supply, and induce alterations in cell survival signaling and drug sensitivity. We will use biochemical and molecular biology methods to investigate the following specific aims: (1) Investigate mtDNA mutations as a genetic basis for alteration of energy metabolism. We will establish innovative experimental systems to test the hypothesis that mtDNA mutations, caused by both endogenous ROS stress and exogenous DNA-damaging agents, lead to malfunction of mitochondrial respiration, increased dependency on glycolysis, and increased superoxide generation. Primary cancer cells from patients will be used to test the clinical relevance of this hypothesis. (2) Investigate the role of mtDNA mutations in altering cell survival and drug sensitivity. We will characterize the profile of drug response in cells with mitochondrial mutations, and identify anticancer agents that are either effective or ineffective in killing cancer cells with mitochondrial respiration defects. Defined experimental model systems with cells containing normal or mutated mitochondria will be established to further test the cause-effect relationship between mtDNA mutations and drug sensitivity, and to investigate the underlying mechanisms. (3) Design and test novel strategies to target the metabolic defects in cancer cells and the associated survival mechanisms to preferentially kill the malignant cells. We will test the ability of novel agents to inhibit glycolysis, preferentially deplete ATP supply in cancer cells, and cause cell death. We will also develop strategies to inhibit cell survival pathways in cancer cells, and explore the possibility of using ROS-mediated mechanism to preferentially kill cancer cells based on their increased oxidative stress associated with mtDNA mutations. We hope that this research will provide new mechanistic insights into the fundamental metabolic alterations in cancer cells, and offer new therapeutic strategies to selectively and effectively kill cancer cells.

描述（由申请人提供）：长期以来，人们已经认识到癌细胞和正常细胞具有不同的能量代谢模式。一个长期且突出的观察结果是，即使存在足够的氧气供应，癌细胞也会显示出糖酵解的增加，这是一种称为沃伯格效应的现象。尽管在广泛的人类癌症中一直观察到对ATP供应的糖酵解的依赖性增加，但造成这种代谢改变的生化和分子机制，其治疗意义仍尚待阐明。包括我们的实验室在内的几个组的最新研究表明，线粒体DNA（mtDNA）经常在人类癌细胞中突变，与药物敏感性的改变有关。由于线粒体在ATP产生和凋亡中都起着重要作用，因此我们假设线粒体DNA突变以及线粒体呼吸链的随之而导致的故障导致ATP产生的降低导致通过氧化磷酸化来减少ATP的产生，从而迫使恶性细胞增强了糖化剂的良好症状，从而促进了糖化剂量的变化，并在良好的启动中生存了良好的变性。我们将使用生化和分子生物学方法来研究以下特定目的：（1）研究mtDNA突变作为能量代谢改变的遗传基础。我们将建立创新的实验系统，以检验以下假设：MTDNA突变是由内源性ROS应激和外源性DNA损害剂引起的，导致线粒体呼吸的故障，对糖酵解的依赖性增加，并增加了超氧化物的产生。来自患者的原发性癌细胞将用于检验该假设的临床相关性。 （2）研究mtDNA突变在改变细胞存活和药物敏感性中的作用。我们将表征有线粒体突变细胞中药物反应的特征，并鉴定出在杀死具有线粒体呼吸缺陷的癌细胞时有效或无效的抗癌剂。将建立具有含有正常线粒体或突变线粒体的细胞的定义的实验模型系统，以进一步测试mtDNA突变与药物敏感性之间的因果关系，并研究基本机制。 （3）设计和测试新型策略，以靶向癌细胞中代谢缺陷以及优先杀死恶性细胞的相关生存机制。我们将测试新型药物抑制糖酵解，优先耗尽癌细胞中ATP供应并导致细胞死亡的能力。我们还将制定抑制癌细胞中细胞存活途径的策略，并探讨使用与MTDNA突变相关的氧化应激，使用ROS介导的机制优先杀死癌细胞的可能性。我们希望这项研究能够为癌细胞的基本代谢改变提供新的机械见解，并提供新的治疗策略，以选择性地有效地杀死癌细胞。