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: 6730145
• 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/6730145
• 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）的敏感性/耐药基础来改善胶质瘤的治疗，替莫唑胺是一种在胶质瘤治疗中重要的化疗药物。众所周知，胶质瘤对TMZ的敏感性/抗性受到TMZ诱导的DNA损伤程度和肿瘤修复这种损伤的能力的影响。然而，胶质瘤对TMZ的敏感性/抗性也受到G2细胞周期检查点的影响，其激活可以将TMZ诱导的DNA损伤与TMZ诱导的细胞毒性分离开来。TMZ诱导的G2检查点部分由Chk1途径控制，Chk1途径的激活导致Cdc2/Cyclin B复合物的磷酸化，G2阻滞和保护免受TMZ毒性。我们最近发现的证据表明，涉及p38应激激酶的第二种独立途径也可能控制TMZ诱导的G2阻滞，进而控制TMZ的敏感性/抗性。尽管它在控制TMZ敏感性/耐药性方面具有潜在的重要性，但p38途径的激活和激活的后果，以及它与Chk1途径的相互作用和治疗操作的潜力仍不清楚。我们假设1)p38通路在TMZ暴露后被DNA错配修复诱导的DNA单链断裂激活；2)DNA损伤传感器c-abl、53BP1、ATM和/或ATR将mmr诱导的DNA损伤与p38激活联系起来；3)激活的p38通过抑制cdc25b和/或Cdc25C以及Cdc2-cyclin B复合物的核活性，有助于启动TMZ诱导的G2阻滞。4) p38通过对p53-和p21依赖性Cdc2的影响，参与tmz诱导的G2阻滞的维持