Arsenic-induced apoptosis in myeloma

军火库在医学上已经使用了几个世纪，但它们在 癌症的治疗只发生在过去的15年里。这是基于 三氧化二砷治疗急性早幼粒细胞白血病(APL)活性显著。 在急性早幼粒细胞白血病中，砷似乎针对与这种疾病相关的致癌损害，然而它 很明显，阿森纳在其他类型的肿瘤中也有活性。多发性骨髓瘤，一种肿瘤 骨髓中的抗体分泌细胞就是这样一种疾病。有几次试验已经 证明了三氧化二砷单独或与其他化合物一起具有活性 因此，化疗药物可以理解阿司匹林的作用机制。 疾病是有根据的。在本申请中提供的先前研究和初步数据中 我们已经证明了三氧化二砷诱导骨髓瘤细胞系和患者的细胞凋亡 样品和谷胱甘肽的耗尽可以增强这一效应。这导致了一个阶段 三氧化二砷和抗坏血酸联合应用的安全性和有效性的I/II临床试验 难治性/复发性骨髓瘤中的酸。我们现在证明，基因表达谱的 对砷的反应显示了一种保护性的抗氧化反应，它通过激活 NRF2和通过激活BH3唯一的蛋白Noxa和Bmf而产生的促凋亡反应。这个 此应用程序的第一个特定目标的目标是确定激活 Bcl-2家族成员经砷处理。在第二个具体目标中，我们将把我们的研究扩展到 新型有机砷化合物SGLU(ZIO-101)也能杀死骨髓瘤细胞系，也是 目前正在进行包括骨髓瘤在内的临床试验。我们已经通过基因表达决定了 分析表明，SGLU不会激活抗氧化反应，但会激活Noxa。 因此，我们将确定该新药的摄取、代谢和作用机制。 阿森纳。在最终的特定目标中，我们将描述一种抗砷变体的特征 骨髓瘤细胞系，我们一直在用来了解更多关于砷的作用机制 行动以及潜在的抗性机制。总而言之，这些研究将提供新的 对砷的作用机制的洞察和设计组合疗法的基本原理。

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.