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（由申请人提供）：该提案的目的是在糖皮质激素（例如地塞米松（DEX））和MEK抑制剂（如PD184352）中建立临床前的证据，以诱导急性淋巴细胞性白血病（所有）细胞。糖皮质激素（GC）代表许多化学治疗方案的常见成分，包括所有淋巴性恶性肿瘤。 GC诱导的凋亡涉及固有的线粒体依赖性途径，但是与GC诱导的细胞死亡有关的信号通路和下游靶分子尚不完全清楚。我们和其他人先前已经表明，BIM（Bcl-2相互作用的细胞死亡中介质）是一种促凋亡的Bcl-2家族蛋白，在所有细胞中都被DEX治疗上调，并且在DEX诱导的细胞凋亡中起着至关重要的作用。此外，BIM被细胞外信号调节激酶（ERK）介导的磷酸化因生存/生长因子而灭活。因此，我们假设与DEX和MEK/ERK抑制剂共同治疗将通过BIM上调和激活促进所有细胞中的凋亡，从而导致细胞死亡。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DEX致死性。现在，我们建议阐明MEK/ERK抑制增强BIM和PERTURBS其他促和抗凋亡的Bcl-2家族成员的活性以提高所有细胞中DEX功效的机制。具体目的是1）评估BIM依赖性/独立途径的重要性以及与DEX和MEK抑制剂共同处理中凋亡中BIM磷酸化状态的重要性； 2）确定地塞米松处理如何诱导BIM的分子机制； 3）采用所有人的体内鼠模型来建立该战略功效的基础。主要概念是我们有一种新颖且潜在的有效方法来增加针对白血病细胞的GC活性，这可能反映了a）GC上调BIM的事实； b）药物MEK抑制剂通过阻断BIM磷酸化和降解进一步增强BIM激活。从该提案中得出的信息将为未来改善糖皮质激素的活性（例如地塞米松）的活性提供合理的基础，并具有临床相关的药理学MEK抑制剂，以治疗所有和其他血液学恶性肿瘤。