Arsenic-induced apoptosis in myeloma

描述(申请人提供)：军火库在医学上已经使用了几个世纪，但它们在癌症治疗中的重新出现只发生在最近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)方面的显著活性。在APL中，砷似乎针对与这种疾病相关的致癌损害，但很明显，砷化合物在其他类型的肿瘤中也有活性。多发性骨髓瘤是一种骨髓抗体分泌细胞的肿瘤，就是这样一种疾病。一些试验已经证明，三氧化二砷单独或与其他化疗药物联合使用具有活性，因此有必要了解砷化合物在本病中的作用机制。在先前的研究和本申请中提供的初步数据中，我们已经证明了三氧化二砷可以诱导骨髓瘤细胞株和患者样本的凋亡，而谷胱甘肽的耗尽可以增强这一作用。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，对砷的反应的基因表达谱既显示了通过激活Nrf2进行的保护性抗氧化反应，也显示了通过激活仅BH3蛋白Noxa和Bmf进行的促凋亡反应。本申请的第一个特定目标是确定砷激活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化合物SGLU(ZIO-101)，它也可以杀死骨髓瘤细胞系，目前也在包括骨髓瘤在内的临床试验中。我们已经通过基因表达谱确定SGLU不激活抗氧化反应，但确实激活Noxa。因此，我们将确定这种新型砷的摄取、代谢和作用机制。在最后的特定目标中，我们将描述一种骨髓瘤细胞系的耐砷变体，我们一直使用该变体来了解更多关于砷的作用机制以及潜在的耐药机制。总而言之，这些研究将为砷的作用机制和设计组合疗法的理论基础提供新的见解。公共卫生意义：三氧化二砷被FDA批准用于治疗急性早幼粒细胞白血病(APL)，并正在对其他几种疾病进行测试，包括骨髓癌和多发性骨髓瘤。虽然APL的作用机制已经很清楚，但为什么其他癌症对这种药物敏感仍不清楚。我们已经确定了三氧化二砷在骨髓瘤细胞中激活的两条途径，一条可以保护细胞，另一条可以杀死细胞，现在将确定每一条途径的作用，并确定正在临床试验中的一种新的基于砷的治疗剂的作用机制。

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.