Mitochondrial Dysfunction and Chemoresistance in Malignant Gliomas

恶性胶质瘤的线粒体功能障碍和化疗耐药

• 批准号: 7787101
• 负责人: Corinne E. Griguer
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787101
• 关键词: ABCB1 gene; Address; Apoptosis; Basic Science; Biochemical; Bioenergetics; Biology; Brain Neoplasms; Carmustine; Cell Cycle; Cell Line; Cell model; Cells; Chemotherapy-Oncologic Procedure; Clinical; Code; Complex; Data; Development; Diagnostic; Disease; Employee Strikes; Exhibits; Failure; Foundations; Free Radicals; Frequencies; Future; Gene Mutation; Generations; Glioblastoma; Glioma; Glycoproteins; Goals; Grant; Growth; Human; Impairment; Intercalating Agents; Intracranial Neoplasms; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Membrane Potentials; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modality; Modeling; Molecular; Multi-Drug Resistance; Multidrug Resistance Induction; Multidrug Resistance-Associated Proteins; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; P-Glycoprotein; P-Glycoproteins; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Primary Brain Neoplasms; Process; Production; Proteins; Proteome; Proteomics; Radiation therapy; Radiosurgery; Recurrence; Regimen; Regulation; Relapse; Relative (related person); Research; Research Design; Research Personnel; Research Proposals; Resistance; Respiration; Role; Stress; Testing; Therapeutic; Transcript; Tumorigenicity; Up-Regulation; base; cancer cell; cell growth; chemotherapy; cytotoxicity; effective therapy; glioma cell line; improved; insight; loss of function; major vault protein; malignant breast neoplasm; mitochondrial dysfunction; mitochondrial membrane; neoplastic; neoplastic cell; novel; novel therapeutics; protein expression; public health relevance; repaired; response; successful intervention; temozolomide; therapeutic target; tumor

DESCRIPTION (provided by applicant): Mitochondria play a central role in cellular energy production, apoptosis and free radical generation. Mitochondrial malfunctions have been associated with development of many cancers, including brain tumors. Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality is exemplified by a median survival of 12-15 months. Current management consists of a combination of surgery, radiotherapy and chemotherapy. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a multidrug-resistance (MDR) phenotype. We previously described in detail the bioenergetic pathways central to glioma growth and progression. One of the most striking observations is that glioma cells which rely on glycolytic metabolism readily adapt to bioenergetic stress by engaging their mitochondrial pathway in order to survive and grow. This suggests that mitochondrial function plays a critical role in the biology of gliomas. The role that mitochondrial dysfunction has in development of the MDR phenotype in brain tumors is unknown. Our goal in this exploratory grant is to confirm and extend our preliminary findings that defective mitochondrial function supports development of the MDR phenotype that leads to progression of malignant brain tumors. Long-term, we believe this will inform development of rational therapeutic and diagnostic strategies that can be applied effectively to this disease. We will test our central hypothesis that impairment of mitochondrial function drives development of the MDR phenotype in glioma by achieving three Specific Aims: (1) We will use human glioma cells and isogenic A0 (mtDNA-depleted) derivatives that display increased MDR phenotype to determine: i) relative cellular sensitivities to temozolomide (TZM) and carmustine (BCNU), by investigating drug effects on cell growth and survival, apoptosis and cell cycle distribution; ii) expression pattern of MDR-associated proteins in particular Major Vault Protein (MVP), highly expressed in the A0 model, and; iii) contribution of MVP to MDR. (2) We will examine established, temozolomide-resistant human glioma cells to determine whether mitochondrial function is impaired in chemoresistant glioma cells compared to chemosensitive isogenic cells. We will quantify and compare: i) respiration rates; ii) enzymatic activities of mitochondrial complexes; iii) mitochondrial proteome and iv) MDR associated proteins. (3) We will determine whether mitochondrial dysfunction results in increased expression of MDR-associated proteins via HIF-11 transcriptional activity. These studies will critically examine the contribution of mitochondrial function in development of multidrug- resistance in gliomas and the findings will produce a foundation for future studies to address development of more effective, targeted therapeutic modalities and diagnostic strategies for malignant glioma patients. PUBLIC HEALTH RELEVANCE: It is well-established that malignant gliomas are generally very resistant to chemotherapeutic modalities with minimal improvement in patient progression-free or overall survivals following aggressive regimens. An essential impediment to effective therapy is believed to reside in the Multi-Drug Resistant Phenotype expressed by these cells. Our preliminary data has revealed that impairment of mitochondrial function in glioma cell lines results in a MDR-like phenotype. The relevance of this research lies in our plan to develop a more detailed understanding of the role that mitochondria have in regulation of multidrug-resistance. This information will provide the foundation for subsequent studies designed to develop rational means to improve chemotherapy regimens for brain tumor patients and as such is highly significant.

描述（由申请人提供）：线粒体在细胞能量产生，凋亡和自由基产生中起着核心作用。线粒体故障与包括脑肿瘤在内的许多癌症的发展有关。胶质母细胞瘤多形（GBM）是最常见的原发性颅内肿瘤，其几乎均匀的致死性在12-15个月的中位生存率来体现。当前管理包括手术，放疗和化学疗法的组合。尽管采用了积极的治疗方法，但90％的GBM患者发生了复发。这种不良结果的原因之一是发展多药耐药性（MDR）表型。我们先前详细描述了神经胶质瘤生长和进展中心的生物能途径。最引人注目的观察结果之一是，依赖糖酵解代谢的神经瘤细胞通过吸引其线粒体途径以生存和生长，很容易适应生物能胁迫。这表明线粒体功能在神经胶质瘤的生物学中起关键作用。线粒体功能障碍在脑肿瘤中MDR表型的发展中具有的作用尚不清楚。我们在这项探索性赠款中的目标是确认和扩展我们的初步发现，即有缺陷的线粒体功能支持MDR表型的发展，从而导致恶性脑肿瘤的发展。长期，我们认为这将为可以有效应用于该疾病的理性治疗和诊断策略的发展发展。 We will test our central hypothesis that impairment of mitochondrial function drives development of the MDR phenotype in glioma by achieving three Specific Aims: (1) We will use human glioma cells and isogenic A0 (mtDNA-depleted) derivatives that display increased MDR phenotype to determine: i) relative cellular sensitivities to temozolomide (TZM) and carmustine (BCNU), by研究药物对细胞生长和生存，凋亡和细胞周期分布的影响； ii）MDR相关蛋白的表达模式，特别是主要的保管蛋白（MVP），在A0模型中高度表达，并且； iii）MVP对MDR的贡献。 （2）我们将检查已建立的替莫唑胺的人神经胶质瘤细胞，以确定与化学敏感性的同源性细胞相比，在化学抗性神经胶质瘤细胞中线粒体功能是否受损。我们将量化和比较：i）呼吸率； ii）线粒体复合物的酶活性； iii）线粒体蛋白质组和IV）MDR相关蛋白。 （3）我们将确定线粒体功能障碍是否通过HIF-11转录活性导致MDR相关蛋白的表达增加。这些研究将批判性地研究线粒体功能在神经胶质瘤中多药耐药性开发中的贡献，这些发现将为将来的研究奠定基础，以解决更有效，有针对性的治疗方式和恶性神经胶质瘤患者的诊断策略。 公共卫生相关性：据此，恶性神经胶质瘤通常对化学治疗方式非常抗性，而在积极方案后，无患者无进展或整体存活率的改善最小。人们认为，有效治疗的基本障碍驻留在这些细胞表达的多药耐药表型中。我们的初步数据表明，神经胶质瘤细胞系中线粒体功能的损害会导致MDR样表型。这项研究的相关性在于我们的计划，即对线粒体在调节多药耐药性中的作用有更详细的了解。该信息将为后续研究提供基础，旨在开发合理的手段来改善脑肿瘤患者的化学疗法方案，因此非常重要。