Arsenic Trioxide activated pathways in malignant cells

三氧化二砷激活恶性细胞通路

• 批准号: 8683116
• 负责人: LEONIDAS C. PLATANIAS
• 金额: $ 25.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683116
• 关键词: Acute Promyelocytic Leukemia; Arsenic; Arsenic Trioxide; Autophagocytosis; Binding; Cell Death; Cell Death Induction; Cells; Clinical; Data; Development; Elements; Event; Exhibits; FDA approved; Feedback; Flavonoids; Future; Generations; Heavy Metals; Hematologic Neoplasms; In Vitro; Induction of Apoptosis; Laboratories; Lead; Leukemic Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Mus; Myeloid Leukemia; Oncogene Proteins; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Property; Proteins; Regulatory Pathway; Resveratrol; Role; Signal Transduction; Stem cells; Therapeutic; Work; base; bcr-abl Fusion Proteins; cancer cell; clinically relevant; in vitro activity; in vivo; in vivo Model; interest; leukemia; leukemic stem cell; member; mouse model; novel; novel strategies; progenitor; research study; response; therapy development; upstream kinase

DESCRIPTION (provided by applicant): This is a competing renewal application whose overall objective is to define the mechanisms of generation of the antileukemic effects of arsenic trioxide (As2O3) and to develop means and ways to enhance its antitumor properties. As2O3 is a heavy metal derivative with potent antileukemic activities in vitro and in vivo and it is highly effective in the treatment of patients with acute promyelocytic leukemia (APL). Despite advances in the field and the high interest to expand the use of arsenic to other hematological malignancies, the precise mechanisms by which As2O3 induces antileukemic responses are not known. We have provided the first evidence that As2O3 -induced autophagy is essential for generation of its suppressive effects on primitive leukemic progenitors from patients with myeloid leukemias. The current proposal is a systematic approach to define the cellular events that lead to As2O3 -dependent autophagy and to identify the mechanisms of autophagy-mediated degradation of oncogenic proteins in primitive leukemic precursors and leukemia initiating stem cells (LICs). Specific aim 1 will examine the mechanisms of As2O3 -autophagy in leukemic progenitor cells. Studies will be performed to identify upstream kinases in the autophagic cascade in leukemia cells and to define the sequence of events leading to their activation in response to arsenic. Other studies will examine the relationship of autophagy with cellular negative feedback regulatory pathways (NFRPs) that are induced in response to As2O3. Specific aim 2 will identify effector mechanisms by which autophagy mediates arsenic- responses on primitive progenitors and leukemia initiating stem cells from patients with AML and CML. Experiments will be performed to define whether autophagy mediates arsenic-dependent degradation of different oncoproteins and to define the precise mechanisms by which this occurs. Other studies will determine whether pharmacological or molecular targeting of elements of the autophagic machinery can enhance arsenic-induced suppression of primitive leukemic precursors and LICs. Specific aim 3 will examine the role of autophagy in arsenic-dependent antileukemic responses in different leukemia mouse models in vivo. It involves experiments to determine whether autophagy is required for the antileukemic properties of As2O3 in vivo and to examine whether other inducers of autophagy exhibit synergistic antileukemic activities with As2O3. Altogether, this work will advance our understanding of the mechanisms by which As2O3 generates antileukemic responses. It should have important clinical-translational implications and possibly lead to the development of novel approaches to target early progenitors and LICs using combinations of As2O3 with other autophagy inducers.

描述（由申请人提供）：这是一项竞争性更新申请，其总体目标是确定三氧化二砷（As 2 O3）抗白血病作用的产生机制，并开发增强其抗肿瘤特性的方法和途径。As_2O_3是一种重金属衍生物，具有较强的体内外抗白血病活性，对急性早幼粒细胞白血病（APL）有较好的治疗作用。尽管在该领域的进展和高度的兴趣，以扩大使用砷到其他血液恶性肿瘤，As 2 O3诱导抗白血病反应的确切机制尚不清楚。我们已经提供了第一个证据表明，As 2 O3诱导的自噬是必不可少的产生其抑制作用的原始白血病祖细胞从髓系白血病患者。目前的建议是一个系统的方法来定义的细胞事件，导致As 2 O3依赖性自噬，并确定在原始白血病前体细胞和白血病起始干细胞（LICs）的致癌蛋白的自噬介导的降解机制。具体目标1将研究白血病祖细胞中As 2 O3-自噬的机制。将进行研究，以确定在白血病细胞中的自噬级联上游激酶，并确定事件的顺序，导致其激活响应砷。其他研究将检查自噬与细胞负反馈调节途径（NFRPs）的关系，这些途径是响应于As 2 O3而诱导的。具体目标2将确定自噬介导对来自AML和CML患者的原始祖细胞和白血病起始干细胞的砷反应的效应器机制。将进行实验，以确定是否自噬介导不同的癌蛋白的砷依赖性降解，并确定发生这种情况的确切机制。其他研究将确定是否药物或分子靶向的元素的自噬机制，可以提高砷诱导的抑制原始白血病的前体和LIC。具体目标3将在体内不同的白血病小鼠模型中检查自噬在砷依赖性抗白血病反应中的作用。它涉及的实验，以确定是否需要自噬的抗白血病性质的三氧化二砷在体内，并检查是否有其他诱导剂的自噬表现出协同抗白血病活性与三氧化二砷。总之，这项工作将推进我们的理解As 2 O3产生抗白血病反应的机制。它应该有重要的临床翻译的影响，并可能导致开发新的方法来靶向早期祖细胞和LICs使用As 2 O3与其他自噬诱导剂的组合。