(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

• 批准号: 9172909
• 负责人: Jung-whan Kim
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172909
• 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; Pathologic; Patients; 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

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 博来霉素已被证明是治疗各种人类癌症的有效化疗剂， 特别是当与其他药剂组合时，并且可以达到高达90%的治愈率。然而，其功效是 严重的肺毒性大大阻碍了它的发展。10%接受博来霉素治疗的癌症患者 致命的肺纤维化目前尚无有效的肺纤维化治疗方法。霉素致 肺纤维化的特征在于成肌纤维细胞活化，其反过来产生过量的 细胞外基质缺氧是严重组织损伤的重要组成部分，如纤维化，由于 血管受损和高代谢需求的渗透细胞的耗氧量增加。 低氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）是低氧环境下心肌重塑的主要调控因子。HIF-1 信号转导与严重的组织损伤和纤维化有关，然而，调节这些信号转导的分子机制尚不清楚。 缺氧微环境中成纤维细胞/肌成纤维细胞对纤维化进展的贡献 我们对此知之甚少。我们试图确定成纤维细胞缺氧信号与细胞凋亡之间的关系。 利用条件性敲除系统（其中Hif-1 α基因被 在成纤维细胞中特异性消融，成纤维细胞是促成肺纤维化发病的基本细胞。 成纤维细胞特异性HIF-1 α缺失或HIF-1 α靶点丙酮酸脱氢酶的药理学抑制 激酶1（PDK1），一种通过抑制线粒体糖酵解而增强细胞糖酵解通量的线粒体激酶 呼吸，导致博来霉素诱导的肌成纤维细胞活化和纤维化的显着减少 进展二氯乙酸盐（DCA）是一种PDK抑制剂，可有效抑制纤维化进展。这些 这些发现使我们假设成纤维细胞HIF-1/PDK轴通过以下途径促进促纤维化进展： PDK介导的糖酵解代谢重编程可作为治疗靶点 对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 糖酵解重编程促进成肌纤维细胞活化和分化。利用肿瘤/肺 目的2还将表征博来霉素和DCA的潜在协同抗癌活性， DCA的抗纤维化作用。我们提出的研究将具体描绘成纤维细胞缺氧 强调HIF-1/PDK介导的代谢重编程在纤维化过程中的反应。这 以前未描述的成纤维细胞中的代谢改变可用作新的治疗策略， 预防肺毒性和纤维化，特别是考虑到DCA已成功和安全地用于 30多年来，它一直被用于治疗代谢紊乱的人类，最近正在评估它是否能靶向治疗癌症。 这使得博来霉素治疗的癌症患者的便利的临床应用合理化。本研究 这将导致在许多领域中更有效和更安全的博来霉素联合方案的创新设计， 通过提高抗癌效果并同时防止其致命的肺部副作用来治疗人类癌症。