Arsenic-induced apoptosis in myeloma

描述（由申请人提供）：砷在医学中的应用已有数百年历史，但它们在癌症治疗中的重新出现只是在过去 15 年。这是基于三氧化二砷在治疗急性早幼粒细胞白血病（APL）中的显着活性。在 APL 中，砷似乎针对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具有活性。多发性骨髓瘤是一种这样的疾病，它是一种骨髓抗体分泌细胞的肿瘤。多项试验表明，三氧化二砷单独或与其他化疗药物联合使用均具有活性，因此有必要了解砷在这种疾病中的作用机制。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会诱导骨髓瘤细胞系和患者样本中的细胞凋亡，并且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，砷反应的基因表达谱表明，通过激活 Nrf2 产生保护性抗氧化反应，并通过激活 BH3 蛋白 Noxa 和 Bmf 产生促凋亡反应。本申请第一个具体目标的目标是确定砷激活 Bcl-2 家族成员的机制。在第二个具体目标中，我们将把我们的研究扩展到一种新型有机砷，SGLU (ZIO-101)，它也可以杀死骨髓瘤细胞系，目前也正在进行包括骨髓瘤在内的临床试验。我们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吸收、代谢和作用机制。在最后的具体目标中，我们将描述一种骨髓瘤细胞系的抗砷变体，我们一直使用该细胞系来更多地了解砷的作用机制以及潜在的抗性机制。这些研究将为砷的作用机制和联合疗法的设计原理提供新的见解。公共健康相关性：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)，并且正在对包括骨髓癌、多发性骨髓瘤在内的几种其他疾病进行测试。虽然 APL 的作用机制已明确，但仍不清楚为什么其他癌症对该药物敏感。我们已经确定，骨髓瘤细胞中的三氧化二砷可激活两种途径，一种可以保护细胞，另一种可以杀死细胞，现在将定义这些途径中每一种的作用，并确定正在临床试验中测试的新型砷基治疗剂的作用机制。

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.