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

• 批准号: 7651709
• 负责人: Hisashi Harada
• 金额: $ 24.79万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651709
• 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; Extracellular Signal Regulated Kinases; Family; Family member; Foundations; Future; Genetic; Genetic Transcription; Glucocorticoid-induced apoptosis; Glucocorticoids; Goals; Growth Factor; Hematologic Neoplasms; Human; In Vitro; Induction of Apoptosis; Laboratories; 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; Principal Investigator; Process; Protein Family; Proteins; Resistance; Role; Severe Combined Immunodeficiency; Signal Pathway; Stimulus; Therapeutic; Treatment Protocols; Up-Regulation; Xenograft Model; base; clinically relevant; cytochrome c; improved; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mouse model; multicatalytic endopeptidase complex; mutant; novel; pre-clinical; prevent; programs; public health relevance; response; synergism; tumor

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. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: The main concept is that we have a novel and potentially effective way to increase glucocorticoids (GC) activity against acute lymphoblastic leukemia (ALL) cells, which may reflect the fact that a) GC up-regulate a pro-death molecule, BIM; and b) pharmacologic MEK/ERK inhibitors further potentiate BIM activation. In this proposal, we will establish the mechanistic evidence how MEK/ERK-BIM pathway involves the synergistic interaction of dexamethasone (Dex) and MEK/ERK inhibitors. Information derived from this proposal will provide a rational foundation for future attempts to improve the activity of glucocorticoids such as Dex with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.

描述（由申请人提供）：本提案的目的是建立糖皮质激素（如地塞米松 (Dex)）和 MEK 抑制剂（如 PD184352）在诱导急性淋巴细胞白血病 (ALL) 细胞凋亡方面的协同作用的临床前证据。糖皮质激素 (GC) 是许多淋巴恶性肿瘤（包括 ALL）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性途径，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。我们和其他人之前已经证明，BIM（BCL-2 细胞死亡相互作用介导物）是一种促凋亡的 BCL-2 家族蛋白，在 ALL 细胞中通过 Dex 处理上调，并在 Dex 诱导的细胞凋亡中发挥重要作用。此外，BIM 会被生存/生长因子介导的细胞外信号调节激酶 (ERK) 磷酸化失活。因此，我们假设 Dex 和 MEK/ERK 抑制剂联合治疗将通过 BIM 上调和激活促进 ALL 细胞凋亡，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 抑制剂可协同促进多种 ALL 细胞系中的 DEX 致死率。我们现在建议阐明 MEK/ERK 抑制增强 BIM 活性并扰乱其他促凋亡和抗凋亡 BCL-2 家族成员以增强 ALL 细胞中 Dex 功效的机制。具体目的是1）评估BIM依赖/独立途径和BIM磷酸化状态在Dex和MEK抑制剂联合治疗的细胞凋亡中的重要性； 2）确定地塞米松治疗诱导BIM的分子机制； 3) 采用 ALL 体内小鼠模型为该策略的功效奠定基础。主要概念是我们有一种新颖且潜在有效的方法来增加 GC 对白血病细胞的活性，这可能反映了以下事实：a) GC 上调 BIM； b) 药理学 MEK 抑制剂通过阻断 BIM 磷酸化和降解进一步增强 BIM 激活。从该提案中获得的信息将为未来尝试提高糖皮质激素（例如地塞米松）与临床相关药理学 MEK 抑制剂在治疗 ALL 和可能的其他血液恶性肿瘤中的活性提供合理的基础。 PHS 398/2590（修订版 11/07） 页继续 格式页 公共卫生相关性：主要概念是我们有一种新颖且潜在有效的方法来增加糖皮质激素 (GC) 对急性淋巴细胞白血病 (ALL) 细胞的活性，这可能反映以下事实：a) GC 上调促死亡分子 BIM； b) 药理学 MEK/ERK 抑制剂进一步增强 BIM 激活。在本提案中，我们将建立 MEK/ERK-BIM 通路如何涉及地塞米松 (Dex) 和 MEK/ERK 抑制剂协同相互作用的机制证据。从该提案中获得的信息将为未来尝试提高糖皮质激素（例如 Dex）与临床相关药理学 MEK 抑制剂在治疗 ALL 和可能的其他血液恶性肿瘤中的活性提供合理的基础。