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.

项目概要/摘要 淋巴水肿是乳腺癌放射和/或手术后的主要并发症。不幸的是，有 没有药物可以有效治疗它。严重的并发症包括疼痛、淋巴管炎、蜂窝组织炎、溃疡和 恶性淋巴管肉瘤的发展。阿霉素 (DOX) 是一种中枢化疗药物 治疗乳腺癌，但会使淋巴水肿的风险增加 4 至 5 倍。 DOX 的作用机制 导致淋巴水肿发生的因素尚不清楚，但据认为与其细胞毒性作用有关。 然而，我们提出DOX的临床浓度直接抑制淋巴节律性收缩 将淋巴液从组织推回到心脏以防止淋巴水肿的血管（LV）。这些宫缩 受到 LV 中钙浓度和氧化还原状态的严格控制。高分辨率体内成像 研究表明，全身施用 DOX 会显着减少淋巴流量。左心室收缩的抑制 DOX 的功能在很大程度上被丹曲林 (DANT) 所阻止，丹曲林 (DANT) 是临床上可用的兰尼定阻滞剂 受体（RYR）和 MitoTEMPO，一种线粒体特异性活性氧（mitoROS）清除剂。 这些数据以及 DOX 激活 RYR 并诱导横纹肌线粒体功能障碍的知识 肌肉和左心室中功能性 RYR 的最新发现使我们做出假设： DOX 会急剧打开 RYR 会增加淋巴肌细胞 (LMC) 中的胞浆钙和 mitoROS，从而导致 左心室收缩并诱发淋巴淤滞和淋巴损伤。据此，我们将探讨是否 DANT 是 FDA 批准的 RYR 阻滞剂，可以预防 DOX 引起的淋巴功能障碍。三个目标将 使用综合技术来探索这一假设，并将依赖于蛋白质和功能分析 分离的淋巴肌细胞和整个左心室，使用光学成像来评估体内淋巴体积流量 对 DOX 和 RYR 阻断的反应，并研究 DANT 作为大鼠乳房潜在治疗方法的效用 肿瘤模型。目标 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 RYR 来增加胞质钙和 mitoROS 的生成作为一种机制 抑制左心室收缩。目标 2 将评估 DANT 是否代表预防 DOX-的潜在治疗选择 抑制淋巴液流动并防止 DOX 引起的淋巴损伤。目标 3 将调查其影响 DANT 对乳腺癌大鼠模型中 DOX 抗癌活性的影响。因此，我们计划探索 RYR DOX 相关淋巴水肿的新治疗靶点并评估 RYR 阻滞剂是否可以重新利用 作为抗淋巴水肿药物。