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Apoptosis Induced by Glucocorticoids and MEK1/2 Inhibitors in Leukemia

糖皮质激素和 MEK1/2 抑制剂诱导白血病细胞凋亡

基本信息

批准号：
8278032
负责人：
Hisashi Harada
金额：
$ 23.74万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278032
关键词：
Acute Lymphocytic Leukemia Apoptosis Apoptosis Regulator Apoptotic BAX gene BCL-2 Protein BCL1 Oncogene BCL2L11 gene Cell Culture Techniques Cell Death Cell Line Cells Cessation of life Combined Modality Therapy Data Dexamethasone Down-Regulation Family Family member Foundations Future Genetic Genetic Transcription Glucocorticoid-induced apoptosis Glucocorticoids Goals Growth Factor Health Hematologic Neoplasms Human In Vitro Induction of Apoptosis Laboratories MAP Kinase Gene MAP2K1 gene MAPK14 gene MEKs Malignant lymphoid neoplasm Mediating Mediator of activation protein Messenger RNA Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Mus Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphorylation Inhibition Play Process Protein Family Proteins Regimen Resistance Role Severe Combined Immunodeficiency Signal Pathway Stimulus Therapeutic Up-Regulation Xenograft Model base clinically relevant cytochrome c improved in vivo inhibitor/antagonist leukemia mouse model multicatalytic endopeptidase complex mutant novel pre-clinical prevent response synergism tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to establish pre-clinical evidence of synergism between glucocorticoids such as dexamethasone (Dex) and the MEK inhibitors such as PD184352 in the induction of apoptosis in acute lymphoblastic leukemia (ALL) cells. Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including ALL. GC-induced apoptosis involves the intrinsic mitochondria-dependent pathway, but the signaling pathways and downstream target molecules involved in GC-induced cell death are not entirely clear. We and others have previously shown that BIM (BCL- 2 Interacting Mediator of cell death), a pro-apoptotic BCL-2 family protein, is up-regulated by Dex treatment in ALL cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation by survival/growth factors. We therefore hypothesize that co-treatment with Dex and MEK/ERK inhibitors will promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. Significantly, preliminary data from our laboratory demonstrate that MEK inhibitors synergistically promote DEX lethality in a variety of ALL cell lines. We now propose to elucidate the mechanisms by which MEK/ERK inhibition enhances the activity of BIM and perturbs other pro- and anti-apoptotic BCL-2 family members to enhance Dex efficacy in ALL cells. The specific aims are to 1) evaluate the significance of BIM-dependent/-independent pathways and the BIM phosphorylation status in apoptosis with Dex and MEK inhibitors co-treatment; 2) determine the molecular mechanisms how BIM is induced by dexamethasone treatment; 3) employ in vivo murine models of ALL to establish a basis for the efficacy of the strategy. The main concept is that we have a novel and potentially effective way to increase GC activity against leukemia cells, which may reflect the fact that a) GCs up-regulate BIM; and b) pharmacologic MEK inhibitors further potentiate BIM activation by blocking BIM phosphorylation and degradation. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as dexamethasone with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.

描述(申请人提供)：这项提案的目标是建立临床前证据，证明糖皮质激素(如地塞米松)和MEK抑制剂(如PD184352)在诱导急性淋巴细胞白血病(ALL)细胞凋亡方面具有协同作用。糖皮质激素(GC)是包括ALL在内的许多淋巴系统恶性肿瘤化疗方案的常见成分。GC诱导的细胞凋亡涉及内在的线粒体依赖途径，但参与GC诱导细胞死亡的信号通路和下游靶分子尚不完全清楚。我们和其他人已经证明，BIM(BCL-2细胞死亡的相互作用介体)是一种促凋亡的BCL-2家族蛋白，在地塞米松诱导的所有细胞中都有上调，并在地塞米松诱导的细胞凋亡中发挥重要作用。此外，细胞外信号调节激酶(ERK)介导的存活/生长因子的磷酸化使BIM失活。因此，我们假设与Dex和MEK/ERK抑制剂联合治疗将通过BIM上调和激活促进所有细胞的凋亡，导致细胞死亡。值得注意的是，我们实验室的初步数据表明，MEK抑制剂在各种细胞系中协同促进地塞米松的致死性。我们现在建议阐明MEK/ERK抑制增强BIM活性和干扰其他促和抗凋亡的bcl2家族成员以增强ALL细胞中Dex疗效的机制。其具体目的是：1)评价地塞米松联合治疗BIM依赖/非依赖途径的意义以及BIM在细胞凋亡中的磷酸化状态；2)确定地塞米松诱导BIM的分子机制；3)采用ALL小鼠体内模型，为该策略的有效性奠定基础。主要的概念是我们有一种新的潜在有效的方法来提高GC对白血病细胞的活性，这可能反映了这样一个事实：a)GC上调BIM；b)药物MEK抑制剂通过阻止BIM的磷酸化和降解进一步增强BIM的激活。从这项建议中获得的信息将为未来的尝试提供合理的基础，以提高地塞米松等糖皮质激素与临床相关的MEK抑制剂在治疗ALL和可能的其他血液系统恶性肿瘤中的活性。