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

基本信息

  • 批准号:
    7787101
  • 负责人:
  • 金额:
    $ 19.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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、细胞凋亡和自由基产生中起核心作用。线粒体功能障碍与包括脑肿瘤在内的许多癌症的发展有关。多形性胶质母细胞瘤(GBM)是最常见的原发性颅内肿瘤,其死亡率几乎一致,中位生存期为12-15个月。目前的治疗包括手术、放疗和化疗相结合。尽管采用积极的治疗方法,90%的GBM患者仍会复发。这种不良结果的一个原因是多药耐药表型的发展。我们之前详细描述了神经胶质瘤生长和进展的生物能量通路。最引人注目的观察结果之一是,依赖糖酵解代谢的胶质瘤细胞很容易通过参与线粒体途径来适应生物能量压力,以便生存和生长。这表明线粒体功能在神经胶质瘤的生物学中起着至关重要的作用。线粒体功能障碍在脑肿瘤中MDR表型发展中的作用尚不清楚。我们探索性资助的目的是确认和扩展我们的初步发现,即线粒体功能缺陷支持MDR表型的发展,导致恶性脑肿瘤的进展。从长远来看,我们相信这将为合理的治疗和诊断策略的发展提供信息,这些策略可以有效地应用于这种疾病。我们将通过实现三个特定目标来验证我们的中心假设,即线粒体功能损伤驱动胶质瘤中MDR表型的发展:(1)我们将使用显示MDR表型增加的人类胶质瘤细胞和等基因A0 (mtdna缺失)衍生物来确定:i)通过研究药物对细胞生长和存活、凋亡和细胞周期分布的影响,来确定替莫唑胺(TZM)和卡莫汀(BCNU)的相对细胞敏感性;ii)耐多药相关蛋白的表达模式,特别是在A0模型中高表达的Major Vault Protein (MVP);iii) MVP对MDR的贡献。(2)我们将检查已建立的替莫唑胺耐药的人类胶质瘤细胞,以确定与化学敏感等基因细胞相比,化疗耐药胶质瘤细胞的线粒体功能是否受损。我们将量化和比较:i)呼吸速率;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)我们将通过HIF-11的转录活性来确定线粒体功能障碍是否会导致耐多药相关蛋白的表达增加。这些研究将严格检查线粒体功能在胶质瘤多药耐药发展中的作用,这些发现将为未来的研究奠定基础,以解决恶性胶质瘤患者更有效,更有针对性的治疗方式和诊断策略的发展。

项目成果

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Corinne E. Griguer其他文献

Targeting glioblastoma multiforme cells with pharmacological ascorbate: Disrupting DNA damage response and mTOR cascades emvia/em extracellular Hsub2/subOsub2/sub
用药理抗坏血酸靶向多形性胶质母细胞瘤细胞:通过细胞外 H₂O₂ 破坏 DNA 损伤反应和 mTOR 级联反应
  • DOI:
    10.1016/j.freeradbiomed.2025.06.008
  • 发表时间:
    2025-09-01
  • 期刊:
  • 影响因子:
    8.200
  • 作者:
    Naphat Chantaravisoot;Kittipong Sanookpan;Onsurang Wattanathamsan;Rungnapa Bootsri;Tankun Banlue;Chatchapon Chuenjit;Nuttiya Kalpongnukul;Claudia R. Oliva;Corinne E. Griguer;Visarut Buranasudja
  • 通讯作者:
    Visarut Buranasudja

Corinne E. Griguer的其他文献

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{{ truncateString('Corinne E. Griguer', 18)}}的其他基金

Mitochondria electron transport chain complexes adaptative responses to cellular stress
线粒体电子传递链复合对细胞应激的适应性反应
  • 批准号:
    10732145
  • 财政年份:
    2023
  • 资助金额:
    $ 19.12万
  • 项目类别:
Paracrine Signaling in Glioma: Bioenergetics Heterogeneity and Chemoresistance
神经胶质瘤中的旁分泌信号传导:生物能异质性和化疗耐药性
  • 批准号:
    9221192
  • 财政年份:
    2016
  • 资助金额:
    $ 19.12万
  • 项目类别:
Cytochrome C Oxidase in Malignant Gliomas
恶性胶质瘤中的细胞色素 C 氧化酶
  • 批准号:
    9027806
  • 财政年份:
    2012
  • 资助金额:
    $ 19.12万
  • 项目类别:
Cytochrome C Oxidase in Malignant Gliomas
恶性胶质瘤中的细胞色素 C 氧化酶
  • 批准号:
    8297145
  • 财政年份:
    2012
  • 资助金额:
    $ 19.12万
  • 项目类别:
Cytochrome C Oxidase in Malignant Gliomas
恶性胶质瘤中的细胞色素 C 氧化酶
  • 批准号:
    8828116
  • 财政年份:
    2012
  • 资助金额:
    $ 19.12万
  • 项目类别:
Cytochrome C Oxidase in Malignant Gliomas
恶性胶质瘤中的细胞色素 C 氧化酶
  • 批准号:
    8464672
  • 财政年份:
    2012
  • 资助金额:
    $ 19.12万
  • 项目类别:
Cytochrome C Oxidase in Malignant Gliomas
恶性胶质瘤中的细胞色素 C 氧化酶
  • 批准号:
    8643090
  • 财政年份:
    2012
  • 资助金额:
    $ 19.12万
  • 项目类别:
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:
    8007374
  • 财政年份:
    2010
  • 资助金额:
    $ 19.12万
  • 项目类别:

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