Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia

化疗增强癌症恶病质肌肉萎缩的机制

• 批准号: 10362568
• 负责人: YI-PING LI
• 金额: $ 41.73万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362568
• 关键词: Address; Animals; C26 tumor; Cachexia; Cancer Model; Cancer Patient; Catabolism; Chemosensitization; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Clinical Research; Colon Carcinoma; Complication; Data; Development; Dose; Drug usage; Etiology; FDA approved; Fluorouracil; Functional disorder; Future; Genetic Transcription; Human; Impairment; In Vitro; Inflammatory; Intervention; Investigational Therapies; Knowledge; Lewis Lung Carcinoma; Mainstreaming; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic Diseases; Mitochondria; Modeling; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fatigue; Muscle Proteins; Muscular Atrophy; NF-kappa B; Omeprazole; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Proton Pump Inhibitors; Quality of life; Serum; Signal Transduction; Skeletal Muscle; TLR4 gene; Testing; Therapeutic; Toxic effect; Toxicity due to chemotherapy; Treatment Protocols; Ubiquitin; Up-Regulation; antagonist; base; cancer cachexia; cancer cell; cancer survival; cancer therapy; chemotherapy; cytokine; design; experience; extracellular vesicles; in vivo; mitochondrial dysfunction; mortality; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; prevent; protein degradation; success; treatment strategy; tumor; vesicular release; wasting

Summary Chemotherapy is a mainstream treatment for most cancers, despite recent progress in the development of new therapies for cancer. A well-documented long lasting toxicity of some chemotherapy agents is their capacity to cause or intensify muscle wasting and fatigue in cancer patients, which are manifestations of cachexia. Cachexia is a metabolic disorder contributing significantly to cancer-related morbidity and mortality due to systemic wasting, as well as decreasing the efficacy while increasing the toxicity of chemotherapy. Consequently, patients suffering from chemotherapy-related muscle wasting may experience difficulty adhering to or completing treatment regimens and may require delays in treatment, dose limitation, or discontinuation of therapy. Further, chemotherapy-related muscle wasting and fatigue can persist for months to years after the cessation of chemotherapy. Thus, the interplay between chemotherapy and cachexia is a significant threat to cancer patient survival and quality of life. However, the underlying mechanism of the detrimental effects of chemotherapy on skeletal muscle is poorly understood, and there is no FDA-approved treatment for this chemotherapy toxicity. The current proposal aims to address this clinical paradox by testing a novel hypothesis for the mechanism through which fluorouracil (5-FU) and cisplatin, two widely prescribed chemotherapy agents, promote cancer’s capacity to induce muscle wasting in tumor-bearing mice. Previously, supratherapeutic doses of 5-FU were shown to promote muscle dysfunction directly in cancer-free animals by causing mitochondrial dysfunction and oxidative stress but not activating the ubiquitin-proteasome pathway that mediates muscle protein loss. Given that 5-FU is used in cancer patients, it is necessary to understand whether and how 5-FU promotes muscle wasting at therapeutically relevant doses in cancer hosts. Similarly, cisplatin has been shown to cause muscle dysfunction directly in cancer-free mice at a supratherapeutic dose, but whether and how it promotes muscle wasting in cancer hosts are undefined. These knowledge gaps prevent clinical intervention of chemotherapy- associated cachexia. Based on preliminary data, the current project is designed to test the hypothesis that 5- FU and cisplatin cause or intensify muscle wasting in cancer hosts indirectly by stimulating the intrinsic capacity of cancer cells to induce muscle protein degradation at therapeutic doses, and to elucidate the underlying mechanisms of this action. Leveraging these findings, experimental therapies will be carried out by repurposing existing pharmacological agents that inhibit 5-FU and cisplatin’s capacity to stimulate cancer-induced muscle wasting. If successful, these drugs can be quickly tested in clinical settings for intervention of chemotherapy- associated muscle wasting.

概括 化学疗法是大多数癌症的主流治疗 癌症的疗法。某些化学疗法剂的有据可查的持久毒性是它们的能力 卡希克西亚 是一种代谢性疾病，由于全身性而导致与癌症相关的发病率和死亡率显着 浪费，并降低效率，同时增加化学疗法的毒性。因此，患者 患有化学疗法相关的肌肉浪费可能会遇到困难或完成 治疗方案，可能需要延迟治疗，剂量限制或中断治疗。此外， 停止后，与化学疗法相关的肌肉浪费和疲劳可能会持续数月至几年 化学疗法。这，化学疗法和恶病质之间的相互作用是对癌症患者的重大威胁 生存和生活质量。但是，化学疗法有害影响的潜在机制 骨骼肌的理解很少，并且没有FDA批准的这种化学疗法毒性治疗方法。 当前的提案旨在通过测试新的假设来解决这种临床悖论 氟尿嘧啶（5-FU）和顺铂（两种广泛规定的化学疗法）促进了癌症的癌症 诱导肿瘤小鼠中肌肉浪费的能力。以前，5-FU的上剂量为5-FU 通过引起线粒体功能障碍和 氧化应激，但没有激活介导肌肉蛋白质丧失的泛素 - 蛋白酶体途径。给出 该5-FU用于癌症患者，有必要了解5-FU是否促进肌肉。 在癌症宿主中浪费在治疗剂量上。同样，顺铂已被证明会引起肌肉 直接在上剂量的无癌小鼠中功能障碍，但是否以及如何促进肌肉 癌症宿主中的浪费不确定。这些知识差距可防止化学疗法的临床干预 - 相关的恶病质。基于初步数据，当前项目旨在检验以下假设。 FU和顺铂会通过刺激内在能力间接引起癌症宿主中的肌肉浪费 癌细胞在治疗剂量下诱导肌肉蛋白质降解，并阐明基础 该动作的机制。利用这些发现，将通过重新利用进行实验疗法 现有的药物抑制5-FU和顺铂刺激癌症肌肉的能力 浪费。如果成功，可以在临床环境中快速测试这些药物，以干预化学疗法 - 相关的肌肉浪费。