(PQ9) Prevention of Bleomycin-induced Pulmonary Toxicity by Dichloroacetate (DCA)

(PQ9) 二氯乙酸盐 (DCA) 预防博莱霉素引起的肺部毒性

基本信息

批准号：
9333290
负责人：
Jung-whan Kim
金额：
$ 17.36万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-16 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333290
关键词：
Ablation Adverse effects Affect Animal Model Apoptosis Attenuated Biology Bleomycin Cancer Patient Cell Cycle Arrest Cells Chemotherapy-Oncologic Procedure Clinical DNA Development Dichloroacetate Disease Extracellular Matrix Fibroblasts Fibrosis Genes Genetic Human Hypoxia Injury Investigation Knock-out Lactic Acidosis Lead Lung Lymphoma Malaria Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolic acidosis Metabolism Mitochondria Modeling Molecular Myofibroblast Oxidative Stress Oxygen Consumption PDH kinase Pathogenesis Pathogenicity Pathologic Patients Pharmacology Phosphotransferases Prevention Process Pulmonary Fibrosis Regimen Research Respiration Safety Signal Pathway Signal Transduction System Testicular Carcinoma Testing Therapeutic Tissues Toxic effect Translations cancer cell cancer therapy cell type chemotherapeutic agent clinical application clinical efficacy design drug efficacy effective therapy fibrogenesis hypoxia inducible factor 1 improved indium-bleomycin inhibitor/antagonist innovation novel novel therapeutics pre-clinical prevent pyruvate dehydrogenase response therapeutic target tumor tumor metabolism

项目摘要

PROJECT SUMMARY Bleomycin has proven to be an effective chemotherapeutic agent for the treatment of various human cancers, particularly when combined with other agents, and can achieve up to 90% cure rate. However, its efficacy is significantly hampered by its serious pulmonary toxicity. 10% of cancer patients treated with bleomycin develop fatal pulmonary fibrosis. No effective therapy for pulmonary fibrosis is currently available. Bleomycin-induced pulmonary fibrosis is characterized by myofibroblastic activation, which in turn, produces excessive amounts of extracellular matrix. Hypoxia is a prominent component of severe tissue injuries, such as fibrosis, due to damaged vasculature and increased oxygen consumption from infiltrated cells with high metabolic demands. The remodeling response to hypoxia is controlled primarily by hypoxia-inducible factor-1 (HIF-1). HIF-1 signaling has been implicated in severe tissue injury and fibrosis, yet, molecular mechanisms that regulate the contributions of fibroblasts/myofibroblasts to fibrotic progression in the context of the hypoxic microenvironment are poorly understood. We sought to determine the relationship between fibroblast hypoxic signaling and the development of pulmonary fibrosis utilizing a conditional knock-out system in which the Hif-1α gene is specifically ablated in fibroblasts, the essential cells contributing to the pathogenesis of pulmonary fibrosis. Fibroblast-specific Hif-1α deletion or pharmacological inhibition of HIF-1α target, pyruvate dehydrogenase kinase1 (PDK1), a mitochondrial kinase that enhances cellular glycolytic flux by suppressing mitochondrial respiration, resulted a significant reduction of bleomycin-induced myofibroblast activation and fibrotic progression. Dichloroacetate (DCA), a PDK inhibitor, effectively suppresses fibrotic progression. These findings lead us to hypothesize that fibroblast HIF-1/PDK axis promotes the profibrotic progression by PDK-mediated glycolytic metabolic reprogramming, which can exploited as a therapeutic target against pulmonary fibrotic toxicity. To test this, Aim 1 will determine if fibroblast HIF-1/PDK-mediated glycolytic reprogramming promotes myofibroblastic activation and differentiation. Utilizing a tumor/pulmonary fibrosis model, Aim 2 will characterize potential synergistic anti-cancer activity of bleomycin and DCA, as well as, the anti-fibrotic effects of DCA. Our proposed study will specifically delineate the fibroblast hypoxic response with emphasis on HIF-1/PDK–mediated metabolic reprogramming in the fibrogenic process. This previously undescribed metabolic alteration in fibroblasts can be exploited as a novel therapeutic strategy for preventing pulmonary toxicity and fibrosis especially given that DCA has been used successfully and safely on humans with metabolic disorders for more than 30 years, and is recently being evaluated for targeting cancer metabolism, which rationalizes a facilitated clinical application for bleomycin-treated cancer patients. This study will lead to the innovative design of more effective and safer bleomycin combinational regimens in a number of human cancers by improving anti-cancer effects and preventing its fatal pulmonary side effects simultaneously.

项目摘要事实证明，博来霉素是治疗各种人类癌的有效化学治疗剂，特别是与其他代理结合使用，并且可以达到90％的固化速率。但是，它的效率是严重的肺毒性受到严重阻碍。 10％接受博来霉素治疗的癌症患者发展致命的肺纤维化。目前没有有效的肺纤维化治疗。博来霉素引起的肺纤维化的特征是肌纤维细胞激活，而肌成纤维细胞激活又产生过量的细胞外基质。缺氧是严重组织损伤的重要组成部分，例如纤维化具有高代谢需求的浸润细胞受损的脉管系统受损和氧气消耗增加。对缺氧的重塑反应主要由低氧诱导因子1（HIF-1）控制。 HIF-1 信号传导已在严重的组织损伤和纤维化中浸渍，但分子机制调节在低氧微环境的背景下，成纤维细胞/成纤维细胞对纤维化进展的贡献知之甚少。我们感觉确定成纤维细胞低氧信号与利用有条件的敲除系统的肺纤维化开发，其中HIF-1α基因为特别是在成纤维细胞中烧蚀的必需细胞，这些细胞有助于肺纤维化的发病机理。成纤维细胞特异性HIF-1α缺失或HIF-1α靶标，丙酮酸脱氢酶的药理抑制 Kinase1（PDK1），一种线粒体激酶，通过抑制线粒体来增强细胞糖酵解通量呼吸导致博来霉素诱导的肌纤维细胞激活和纤维化显着降低进展。 PDK抑制剂二氯乙酸（DCA）有效抑制纤维化进展。这些调查结果使我们假设成纤维细胞HIF-1/PDK轴促进了通过 PDK介导的糖酵解代谢重编程，可以作为治疗靶标探索抗肺纤维化毒性。为了测试这一点，AIM 1将确定成纤维细胞HIF-1/PDK介导的糖酵解重编程可促进肌纤维细胞激活和分化。利用肿瘤/肺部纤维化模型，AIM 2还将表征博来霉素和DCA的潜在协同抗癌活性 AS，DCA的抗纤维化作用。我们提出的研究将专门描述成纤维细胞缺氧重点是HIF-1/PDK介导的代谢重编程中的反应。这以前未描述的成纤维细胞中未描述的代谢改变可以作为一种新型的治疗策略防止肺毒性和纤维化，特别是考虑到DCA已成功地安全地使用了患有代谢疾病的人已经30多年了，最近正在评估针对癌症代谢，该代谢合理地为博来霉素治疗的癌症患者提供了促进的临床应用。这项研究将导致更有效，更安全的博来霉素组合方案的创新设计人类癌症通过改善抗癌作用并简单地防止其致命的肺部副作用。