Arsenic-induced apoptosis in myeloma

描述（由申请人提供）：砷剂已在医学中使用了几个世纪，但其在癌症治疗中的重新出现仅发生在过去的15年中。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，砷似乎靶向与这种疾病相关的致癌病变，但很明显，砷剂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使用具有活性，因此有必要了解砷剂在这种疾病中的作用机制。在先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作用。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，基因表达谱的砷反应表明通过激活Nrf 2和促凋亡反应，通过激活BH 3只有蛋白Noxa和BMF的保护性抗氧化反应。本申请的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不激活抗氧化反应，但激活Noxa。因此，我们将确定这种新型砷的摄取，代谢和行动的机制。在最后的具体目标中，我们将描述一种骨髓瘤细胞系的砷耐药变体，我们一直在使用该细胞系来了解更多关于砷的作用机制以及潜在的耐药机制。这些研究将为砷的作用机制和联合治疗的设计提供新的见解。公共卫生相关性：三氧化二砷被FDA批准用于治疗急性早幼粒细胞白血病（APL），并正在测试其他几种疾病，包括骨髓癌多发性骨髓瘤。虽然APL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。我们已经确定了骨髓瘤细胞中三氧化二砷激活的两种途径，一种可能对细胞具有保护作用，另一种可能会杀死细胞，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.