Arsenic-induced apoptosis in myeloma

砷诱导骨髓瘤细胞凋亡

• 批准号: 7751820
• 负责人: Lawrence H. Boise
• 金额: $ 36.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751820
• 关键词: Acute Promyelocytic Leukemia; Antioxidants; Apoptosis; Apoptotic; Arsenic; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Binding; Bone Marrow; Cell Death; Cell Line; Cells; Chimeric Proteins; Clinic; Clinical Trials; Combined Modality Therapy; Data; Disease; Drug resistance; FDA approved; Family member; Gene Expression Profiling; Genes; Glutathione; Goals; Health; Heat-Shock Response; Immunoglobulin-Secreting Cells; Laboratories; Lead; Learning; Lesion; Light; Malignant Neoplasms; Mediating; Medicine; Metabolism; Mitochondria; Multiple Myeloma; Nature; Neoplasms; Noxae; Oncogenic; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Plasma Cell Neoplasm; Proteins; Puma; Refractory; Relapse; Reporting; Resistance; Role; Sampling; Signal Transduction; Solid; Testing; Therapeutic Agents; Translating; Tretinoin; Trixenox; Variant; Work; base; cancer therapy; cell killing; chemotherapeutic agent; clinically relevant; design; effective therapy; improved; insight; killings; leukemia; novel; protein activation; resistance mechanism; response; safety testing; tumor; uptake

DESCRIPTION (provided by applicant): Arsenicals have been used in medicine for centuries however their re-emergence in the treatment of cancer has only occurred in the last 15 years. This has been based on the remarkable activity of arsenic trioxide in the treatment of Acute Promyelocytic Leukemia (APL). In APL, arsenic appears to target the oncogenic lesion associated with this disease, however it is clear that arsenicals have activity in other tumor types. Multiple myeloma, a neoplasia of the antibody secreting cells of the bone marrow is one such disease. Several trials have demonstrated that arsenic trioxide has activity alone and in combination with other chemotherapeutic agents therefore understanding the mechanism of action of arsenicals in this disease is warranted. In previous studies and preliminary data presented within this application we have demonstrated that arsenic trioxide induces apoptosis in myeloma cell lines and patient samples and that depletion of glutathione can enhance this effect. This has resulted in a phase I/II clinical trial to test the safety and efficacy of the combination of arsenic trioxide and ascorbic acid in refractory/relapsed myeloma. We now demonstrate that gene expression profiling of the response to arsenic demonstrates both a protective antioxidant response via the activation of Nrf2 and a pro-apoptotic response via activation of the BH3 only proteins Noxa and Bmf. The goals of the first Specific Aim of this application are to determine the mechanism of activation of Bcl-2 family members by arsenic. In the second Specific Aim we will extend our studies to a novel organic arsenical, SGLU (ZIO-101) that can also kill myeloma cell lines and is also currently in clinical trials including for myeloma. We have determined by gene expression profiling that SGLU does not activate the anti-oxidant response but does activate Noxa. Therefore we will determine the mechanisms of uptake, metabolism and action of this novel arsenical. In the final Specific Aim we will characterize an arsenic-resistant variant of one of the myeloma cell lines that we have been using to learn more about both arsenic mechanism of action as well as potential resistance mechanisms. Together these studies will provide novel insights into arsenical mechanism of action and for rationale designed combination therapies. PUBLIC HEALTH RELEVANCE: Arsenic trioxide is FDA approved for the treatment of the Acute Promyelocytic Leukemia (APL) and is being tested in several other diseases including the bone marrow cancer Multiple Myeloma. While the mechanism of action in APL is well defined it remains unclear why other cancers are sensitive to this agent. We have determined that two pathways are activated by arsenic trioxide in myeloma cells, one that could be protective to the cell and another that would kill the cell and will now define the roles of each of these pathways as well as determine the mechanism of action of a new arsenic-based therapeutic agent that is being tested in clinical trials.

描述（由申请人提供）：砷已经在医学上使用了几个世纪，但它们在治疗癌症方面的重新出现只是在过去的15年里。这是基于三氧化二砷在治疗急性早幼粒细胞白血病（APL）中的显著活性。在APL中，砷似乎靶向与该疾病相关的致癌病变，但很明显砷在其他肿瘤类型中也有活性。多发性骨髓瘤，一种骨髓抗体分泌细胞的肿瘤，就是这样一种疾病。几项试验表明，三氧化二砷单独或与其他化疗药物联合具有活性，因此有必要了解砷类药物在该疾病中的作用机制。在之前的研究和本应用程序中提供的初步数据中，我们已经证明三氧化二砷诱导骨髓瘤细胞系和患者样本的细胞凋亡，而谷胱甘肽的消耗可以增强这种效果。这导致了一项I/II期临床试验，以测试三氧化二砷和抗坏血酸联合治疗难治性/复发性骨髓瘤的安全性和有效性。我们现在证明了砷反应的基因表达谱显示了通过激活Nrf2产生的保护性抗氧化反应和通过激活BH3蛋白Noxa和Bmf产生的促凋亡反应。本应用的第一个特异性目的是确定砷活化Bcl-2家族成员的机制。在第二个特定目标中，我们将把我们的研究扩展到一种新的有机砷，SGLU (ZIO-101)，它也可以杀死骨髓瘤细胞系，目前也在临床试验中，包括骨髓瘤。我们已经通过基因表达谱确定SGLU不会激活抗氧化反应，但会激活Noxa。因此，我们将确定这种新型砷的摄取、代谢和作用机制。在最后的特异性目标中，我们将描述一种骨髓瘤细胞系的砷抗性变体，我们一直在使用它来了解更多关于砷作用机制和潜在抗性机制的信息。总之，这些研究将为砷的作用机制和基本原理设计的联合治疗提供新的见解。公共卫生相关性：三氧化二砷已被FDA批准用于治疗急性早幼粒细胞白血病（APL），并正在对包括骨髓癌多发性骨髓瘤在内的其他几种疾病进行测试。虽然在APL中的作用机制已经明确，但仍不清楚为什么其他癌症对这种药物敏感。我们已经确定，骨髓瘤细胞中有两条途径被三氧化二砷激活，一条可能对细胞有保护作用，另一条可能会杀死细胞，现在我们将确定这两条途径的作用，并确定一种新的砷基治疗剂的作用机制，这种药物正在临床试验中进行测试。