Arsenic-induced apoptosis in myeloma

几个世纪以来，砷剂一直被用于医学，但它们在 癌症的治疗在过去15年才出现。这是基于 三氧化二砷在治疗急性早幼粒细胞白血病（APL）中具有显著的活性。 在APL中，砷似乎靶向与这种疾病相关的致癌病变，然而， 很明显砷剂对其他类型的肿瘤也有作用。多发性骨髓瘤， 骨髓的抗体分泌细胞就是这样一种疾病。几次审判 表明三氧化二砷单独和与其它化合物组合具有活性， 因此，了解砷剂在这一过程中的作用机制， 疾病是必要的。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的凋亡， 样品和谷胱甘肽的耗尽可以增强这种效果。这导致了一个阶段 I/II期临床试验，以测试三氧化二砷和抗坏血酸的组合的安全性和有效性 难治性/复发性骨髓瘤中的酸。我们现在证明，基因表达谱的 对砷的反应表明，通过激活 Nrf 2和通过仅BH 3蛋白Noxa和Bmf的活化的促凋亡反应。的 本申请的第一个具体目的的目标是确定 砷对Bcl-2家族成员的影响。在第二个具体目标，我们将扩大我们的研究， 新型有机砷，SGLU（ZIO-101），也可以杀死骨髓瘤细胞系， 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 分析表明SGLU不激活抗氧化反应，但激活Noxa。 因此，我们将确定这种新的摄取，代谢和作用机制 含砷的在最后的具体目标中，我们将描述一种抗砷变体的特征， 我们一直在使用骨髓瘤细胞系来更多地了解砷的作用机制， 以及潜在的抵抗机制。这些研究将提供新的 深入了解砷的作用机制和合理设计的联合治疗。

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.