Arsenic-induced apoptosis in myeloma

砷诱导骨髓瘤细胞凋亡

基本信息

批准号：
8386638
负责人：
Lawrence H. Boise
金额：
$ 34.11万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386638
关键词：
Acute Promyelocytic Leukemia Antioxidants Apoptosis Apoptotic Arsenic Arsenic Trioxide Arsenicals Ascorbic Acid BCL-2 Protein BCL2 gene 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 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

项目摘要

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.

砷在医学上的使用已有几个世纪的历史，但它们在医学上的重新出现癌症的治疗是最近15年才出现的。这是基于三氧化二砷在治疗急性早幼粒细胞白血病（APL）方面具有显着活性。在 APL 中，砷似乎针对与该疾病相关的致癌病变，但它很明显，砷对其他肿瘤类型也有活性。多发性骨髓瘤，一种肿瘤骨髓抗体分泌细胞就是这样一种疾病。多项试验已证明三氧化二砷单独或与其他物质结合具有活性因此，化疗药物了解砷的作用机制疾病是有保证的。在之前的研究和本申请中提供的初步数据中我们已经证明三氧化二砷可诱导骨髓瘤细胞系和患者的细胞凋亡样品和谷胱甘肽的消耗可以增强这种效果。这导致了一个阶段 I/II 临床试验测试三氧化二砷和抗坏血酸联合用药的安全性和有效性难治性/复发性骨髓瘤中的酸。我们现在证明，基因表达谱对砷的反应表明通过激活 Nrf2 和通过激活 BH3 蛋白 Noxa 和 Bmf 产生的促凋亡反应。这该应用程序的第一个具体目标的目标是确定激活的机制 Bcl-2家族成员受砷影响。在第二个具体目标中，我们将把我们的研究扩展到新型有机砷，SGLU (ZIO-101)，也可以杀死骨髓瘤细胞系，并且目前正在进行包括骨髓瘤在内的临床试验。我们通过基因表达来确定分析表明 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药物的摄取、代谢和作用机制砷。在最后的具体目标中，我们将描述其中一种的抗砷变体我们一直在使用骨髓瘤细胞系来更多地了解砷的机制作用以及潜在的抵抗机制。这些研究共同将提供新颖的深入了解砷的作用机制和设计联合疗法的基本原理。