P38, G2 Arrest, and Temozolomide Resistance in Gliomas

神经胶质瘤中的 P38、G2 逮捕和替莫唑胺耐药性

• 批准号: 6847844
• 负责人: Russell O. Pieper
• 金额: $ 31.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847844
• 关键词: DNA damage; DNA repair; antineoplastics; cell cycle; cell cycle proteins; cell growth regulation; drug resistance; enzyme activity; enzyme inhibitors; enzyme mechanism; genetic manipulation; glioma; laboratory rat; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; phosphorylation; temozolomide; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term objective of this study is to improve the therapy of gliomas by better understanding the basis for sensitivity/resistance to temozolomide (TMZ), a chemotherapeutic agent important in the treatment of gliomas. The sensitivity/resistance of gliomas to TMZ is well known to be influenced by the extent of TMZ-induced DNA damage and by the ability of the tumor to repair this damage. The sensitivity/resistance of gliomas to TMZ is also, however, influenced by the G2 cell cycle checkpoint, activation of which can dissociate TMZ-induced DNA damage from TMZ-induced cytotoxicity. The TMZ-induced G2 checkpoint is controlled in part by the Chk1 pathway, activation of which leads to phosphorylation of the Cdc2/Cyclin B complex, G2 arrest, and protection from TMZ toxicity. We recently uncovered evidence that a second independent pathway involving the p38 stress kinases may also control TMZ-induced G2 arrest and, in turn, TMZ sensitivity/resistance. Despite its potential importance in controlling TMZ sensitivity/resistance, the activation and consequences of activation of the p38 pathway, as well as its interaction with the Chk1 pathway and potential for therapeutic manipulation remain undefined. We hypothesize that 1) the p38 pathway is activated following TMZ exposure by DNA mismatch repair-induced DNA single- strand breaks, 2) the DNA damage sensors c-abl, 53BP1, ATM, and/or ATR link MMR-induced DNA damage to p38 activation, 3) activated p38 contributes to the initiation of TMZ-induced G2 arrest by suppressing nuclear activity of Cdc25 B and/or Cdc25C, and Cdc2-cyclin B complexes, 4) p38 contributes to the maintenance of TMZ-induced G2 arrest by effects on p53- and p21-dependent Cdc2 activation, and 5) inhibition of the p38 and Chk1 pathways will additively or synergistically sensitize glioma cells to TMZ in vitro and in vivo. The results of these studies are expected to lead to a better understanding of the TMZ-induced G2 checkpoint and to identification of ways in which the TMZ-induced G2 checkpoint, and hence TMZ resistance, can be selectively reversed in gliomas.

描述（由申请人提供）：本研究的长期目标是通过更好地了解替莫唑胺（TMZ）（一种在神经胶质瘤治疗中重要的化疗药物）的敏感性/耐药性基础来改善神经胶质瘤的治疗。众所周知，神经胶质瘤对 TMZ 的敏感性/耐药性受到 TMZ 诱导的 DNA 损伤程度以及肿瘤修复这种损伤的能力的影响。然而，神经胶质瘤对 TMZ 的敏感性/耐药性也受到 G2 细胞周期检查点的影响，该检查点的激活可以将 TMZ 诱导的 DNA 损伤与 TMZ 诱导的细胞毒性分离。 TMZ 诱导的 G2 检查点部分由 Chk1 通路控制，该通路的激活导致 Cdc2/Cyclin B 复合物磷酸化、G2 停滞，并防止 TMZ 毒性。我们最近发现的证据表明，涉及 p38 应激激酶的第二条独立途径也可能控制 TMZ 诱导的 G2 停滞，进而控制 TMZ 敏感性/耐药性。尽管其在控制 TMZ 敏感性/耐药性方面具有潜在的重要性，但 p38 通路的激活和激活的后果，以及它与 Chk1 通路的相互作用以及治疗操作的潜力仍不清楚。我们假设 1) p38 通路在 TMZ 暴露后通过 DNA 错配修复诱导的 DNA 单链断裂而被激活，2) DNA 损伤传感器 c-abl、53BP1、ATM 和/或 ATR 连接 MMR 诱导的 DNA 损伤p38 激活，3) 激活的 p38 通过抑制 Cdc25 B 和/或 Cdc25C 的核活性，有助于启动 TMZ 诱导的 G2 停滞，以及Cdc2-细胞周期蛋白 B 复合物，4) p38 通过影响 p53 和 p21 依赖性 Cdc2 有助于维持 TMZ 诱导的 G2 停滞 激活，5) p38 和 Chk1 途径的抑制将在体外和体内额外或协同地使神经胶质瘤细胞对 TMZ 敏感。这些研究的结果预计将有助于更好地理解 TMZ 诱导的 G2 检查点，并确定在神经胶质瘤中选择性逆转 TMZ 诱导的 G2 检查点以及由此产生的 TMZ 耐药性的方法。