The role of AMPK signaling in the anti-leukemic effects of Arsenic Trioxide

AMPK 信号在三氧化二砷抗白血病作用中的作用

• 批准号: 8650044
• 负责人: Elspeth Morrison Beauchamp
• 金额: $ 5.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650044
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Affect; Arsenic; Arsenic Trioxide; Arsenicals; Autophagocytosis; Binding; Bone Marrow Transplantation; Cells; Chromosome abnormality; Clinical; Clinical Trials; Complex; Cysteine; Data; Development; Disease; Feedback; Future; Generations; Goals; High Dose Chemotherapy; In Vitro; Laboratories; Lead; Malignant Neoplasms; Mediating; Modeling; Mus; Myeloid Leukemia; Outcome; Pathway interactions; Patients; Play; Proteins; Regimen; Relapse; Research; Research Proposals; Risk; Role; Signal Pathway; Signal Transduction; Structure; Sulfhydryl Compounds; Testing; Therapeutic; Therapeutic Agents; United States Food and Drug Administration; Work; Xenograft procedure; base; cancer type; clinical efficacy; combinatorial; cytotoxic; human FRAP1 protein; in vivo; leukemia; mouse model; novel; older patient; oxidation; pre-clinical; prevent; public health relevance; treatment effect

DESCRIPTION (provided by applicant): Arsenic trioxide (ATO) is a Food and Drug Administration (FDA) approved therapy for a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL). There is also potential for clinical development of arsenic and/or other medicinal compounds for the treatment of other malignancies. However, to date arsenic has not shown significant clinical activity as a single agent outside of APL, likely due to the activation of negative feedback pathways that counteract its activity. The major goal of our research group is to investigate the mechanisms of action of arsenic in myeloid leukemias, understand the negative feedback pathways activate by arsenic and identify agents that can be combined with it to enhance clinical outcomes in patients. In this proposal we seek to investigate the role of AMPK in the anti-leukemic effects of arsenic and how that contributes to the induction of mTOR as a negative feedback loop as well as in the induction of autophagy. It was previously shown in our laboratory that during treatment of leukemia cells with arsenic there is activation of the mTOR pathway through an unknown mechanism. We have preliminary data to suggest that arsenic directly binds to AMPK and inhibits its activity. Because AMPK is a direct negative regulator of mTOR, we propose that this is an important mechanism for activation of the mTOR pathway by arsenic. In Aim 1 we will investigate how arsenic affects AMPK structure and function. We also propose that arsenic through AMPK inhibition leads to induction of autophagy through the VPS34/Beclin/UVRAG complex since AMPK can negative regulate VSP34. In Aim 2 we will combine arsenic with AMPK activators to investigate the role of AMPK signaling in the induction of anti-leukemic effects of arsenic in vivo in a xenograft mouse model of acute myeloid leukemia (AML). Altogether, this work should define the mechanisms by which arsenic activates negative feedback pathways and may lead to the development of novel agents for the treatment of leukemias.

描述（由申请人提供）：三氧化二砷（ATO）是美国食品药品监督管理局（FDA）批准的治疗急性髓细胞白血病（APL）亚型的药物。砷和/或其他药用化合物用于治疗其他恶性肿瘤的临床开发也有潜力。然而，到目前为止，砷作为APL以外的单一药物尚未显示出显著的临床活性，这可能是由于激活了抵消其活性的负反馈途径。我们研究小组的主要目标是研究砷在髓系白血病中的作用机制，了解砷激活的负反馈途径，并确定可以与之结合以提高患者临床结局的药物。在这项提议中，我们试图研究AMPK在砷的抗白血病作用中的作用，以及它如何作为负反馈回路促进mTOR的诱导以及诱导自噬。我们的实验室先前显示，在用砷治疗白血病细胞期间，存在通过未知机制激活mTOR通路。我们有初步的数据表明砷直接结合AMPK并抑制其活性。由于AMPK是mTOR的直接负调节剂，我们认为这是砷激活mTOR通路的重要机制。在目标1中，我们将研究砷如何影响AMPK的结构和功能。我们还提出，砷通过AMPK抑制导致诱导自噬通过VPS 34/Beclin/UVRAG复合物，因为AMPK可以负调节VSP 34。在目标2中，我们将联合收割机砷与AMPK激活剂结合，以研究AMPK信号传导在急性髓细胞白血病（AML）异种移植小鼠模型中诱导砷体内抗白血病作用中的作用。总之，这项工作应该确定砷激活负反馈途径的机制，并可能导致开发新的药物治疗白血病。