Mechanism and Prevention of Doxorubicin-Induced Lymphedema

阿霉素所致淋巴水肿的机制及预防

基本信息

批准号：
10240512
负责人：
Amanda Stolarz
金额：
$ 27.36万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-24 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10240512
关键词：
Acute Address Apoptosis Back Breast Cancer Model Breast Cancer therapy Calcium Cardiac Myocytes Cellulitis Centers of Research Excellence Clinical Complex Complication Dantrolene Data Development Doxorubicin Extravasation FDA approved Fluid Balance Gene Expression Generations Heart Immune response Impairment Injury Investigation Knowledge Liquid substance Lymph Lymphangitis Lymphatic Lymphatic function Lymphedema Malignant - descriptor Mechanics Mediating Mitochondria Muscle Cells Muscle Fibers Neoplasm Metastasis Occupations Oxidation-Reduction Oxidative Stress Pain Periodicity Pharmaceutical Preparations Preparation Prevention Proteins Radiation Rattus Reactive Oxygen Species Resolution Risk Role Ryanodine Receptors Sarcoplasmic Reticulum Second Primary Cancers Signal Transduction Striated Muscles Techniques Testing Therapeutic Tissues Toxic effect Translating Ulcer anticancer activity base breast surgery cancer therapy cardioprotection chemotherapeutic agent clinically relevant cytotoxic in vivo in vivo imaging lymph flow lymph stasis lymphangiosarcoma lymphatic circulation lymphatic dysfunction lymphatic vasculature lymphatic vessel malignant breast neoplasm mitochondrial dysfunction new therapeutic target novel novel therapeutics optical imaging preservation prevent protein expression receptor expression recurrent infection response tissue injury tumor

Acute Address Apoptosis Back Breast Cancer Model Breast Cancer therapy Calcium Cardiac Myocytes Cellulitis Centers of Research Excellence Clinical Complex Complication Dantrolene Data Development Doxorubicin Extravasation FDA approved Fluid Balance Gene Expression Generations Heart Immune response Impairment Injury Investigation Knowledge Liquid substance Lymph Lymphangitis Lymphatic Lymphatic function Lymphedema Malignant - descriptor Mechanics Mediating Mitochondria Muscle Cells Muscle Fibers Neoplasm Metastasis Occupations Oxidation-Reduction Oxidative Stress Pain Periodicity Pharmaceutical Preparations Preparation Prevention Proteins Radiation Rattus Reactive Oxygen Species Resolution Risk Role Ryanodine Receptors Sarcoplasmic Reticulum Second Primary Cancers Signal Transduction Striated Muscles Techniques Testing Therapeutic Tissues Toxic effect Translating Ulcer anticancer activity base breast surgery cancer therapy cardioprotection chemotherapeutic agent clinically relevant cytotoxic in vivo in vivo imaging lymph flow lymph stasis lymphangiosarcoma lymphatic circulation lymphatic dysfunction lymphatic vasculature lymphatic vessel malignant breast neoplasm mitochondrial dysfunction new therapeutic target novel novel therapeutics optical imaging preservation prevent protein expression receptor expression recurrent infection response tissue injury tumor

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项目摘要

PROJECT SUMMARY/ABSTRACT Lymphedema is a major complication after radiation and/or surgery for breast cancer. Unfortunately, there are no medications to effectively treat it. Serious complications include pain, lymphangitis, cellulitis, ulcers, and the development of malignant lymphangiosarcomas. Doxorubicin (DOX) is a central chemotherapeutic agent for treating breast cancer, but it increases the risk of lymphedema by 4- to 5-fold. The mechanism by which DOX contributes to the development of lymphedema is unknown, but it is thought to relate to its cytotoxic action. However, we propose that clinical concentrations of DOX directly inhibit the rhythmic contractions of lymph vessels (LVs) that propel lymph fluid from tissues back to the heart to prevent lymphedema. These contractions are tightly controlled by the calcium concentration and redox state in LVs. High-resolution in vivo imaging also reveals that systemically administered DOX profoundly reduces lymph flow. The suppression of LV contractile function by DOX is largely prevented by both dantrolene (DANT), a clinically available blocker of ryanodine receptors (RYRs), and MitoTEMPO, a mitochondrial-specific reactive oxygen species (mitoROS) scavenger. These data, along with knowledge that DOX activates RYRs and induces mitochondrial dysfunction in striated muscle and recent discoveries of functional RYRs in LVs, have led us to hypothesize that: DOX acutely opens RYRs to increase cytosolic calcium and mitoROS in lymph muscle cells (LMCs), resulting in the loss of LV contractions and inducing lymphostasis and lymphatic injury. Accordingly, we will explore whether DANT, an FDA-approved RYR blocker, can prevent DOX-induced lymphatic dysfunction. Three aims will use an integration of techniques to explore this hypothesis and will rely on protein and functional analysis of isolated lymph muscle cells and whole LVs, use optical imaging to assess volumetric lymph flow in vivo in response to DOX and RYR blockade, and investigate the utility of DANT as a potential therapeutic in a rat breast tumor model. Aim 1 will quantify the gene and protein expression profiles of RYR subtypes and determine whether DOX activates RYRs to increase cytosolic calcium and mitoROS generation as a mechanism of inhibiting LV contractions. Aim 2 will evaluate if DANT represents a potential therapeutic option to prevent DOX- induced suppression of lymph flow and prevent DOX-induced lymphatic injury. Aim 3 will investigate the effects of DANT on the anticancer activity of DOX in a rat model of breast cancer. Thus, we plan to explore RYRs as new therapeutic targets for DOX-related lymphedema and evaluate whether RYR blockers can be repurposed as anti-lymphedema medications.

项目摘要/摘要淋巴水肿是辐射和/或乳腺癌手术后的主要并发症。不幸的是，那里没有有效治疗的药物。严重的并发症包括疼痛，淋巴管炎，蜂窝炎，溃疡和恶性淋巴管肉瘤的发展。阿霉素（DOX）是一种中央化学治疗剂治疗乳腺癌，但会增加4至5倍的淋巴水肿的风险。 Dox的机制有助于淋巴水肿的发展是未知的，但被认为与其细胞毒性作用有关。但是，我们建议DOX的临床浓度直接抑制淋巴的节奏收缩将淋巴液从组织回到心脏的血管（LVS）以防止淋巴水肿。这些收缩由LVS中的钙浓度和氧化还原状态紧密控制。体内成像中的高分辨率揭示了系统施用的DOX深刻降低了淋巴流量。抑制LV收缩 DANTROLENE（DANT）在很大程度上阻止了Dox的功能，这是ryanodine的临床可用阻滞剂受体（Ryrs）和Mitotempo，一种线粒体特异性活性氧（Moritoros）清除剂。这些数据以及DOX激活Ryrs并引起线粒体功能障碍的知识 LV中功能性RYRS的肌肉和最新发现使我们假设：Dox急性打开瑞尔斯增加淋巴肌肉细胞（LMC）中的胞质钙和身体的鼠标，导致丧失 LV收缩和诱导淋巴结和淋巴损伤。因此，我们将探讨是否 Dant是FDA批准的RYR阻滞剂，可以防止DOX诱导的淋巴功能障碍。三个目标利用技术的整合来探索这一假设，并将依靠蛋白质和功能分析分离的淋巴肌肉细胞和整个LV，使用光学成像评估体内体内体积淋巴流量对DOX和RYR封锁的反应，并研究Dant作为大鼠乳房潜在治疗的实用性肿瘤模型。 AIM 1将量化RYR亚型的基因和蛋白质表达谱并确定 DOX是否激活Ryrs以增加胞质钙和Mitoros的产生抑制LV收缩。 AIM 2将评估Dant是否代表了防止Dox的潜在治疗选择诱导的淋巴流量抑制并防止DOX诱导的淋巴损伤。 AIM 3将调查效果在大鼠乳腺癌模型中，DOX的抗癌活性。因此，我们计划探索Ryrs 与DOX相关淋巴水肿的新治疗靶标，并评估是否可以重新使用RYR阻滞剂作为抗淋巴水肿。