Mechanism and Prevention of Doxorubicin-Induced Lymphedema

阿霉素所致淋巴水肿的机制及预防

• 批准号: 10487486
• 负责人: Amanda Stolarz
• 金额: $ 26.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 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/10487486
• 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; antagonist; 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

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。