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）：这项研究的长期目标是通过更好地理解对替莫唑胺（TMZ）的敏感性/抗性的基础来改善神经胶质瘤的治疗，这是一种对治疗神经胶质瘤很重要的化学治疗剂。众所周知，神经胶质瘤对TMZ的敏感性/耐药性受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/抗性也受G2细胞周期检查点的影响，其激活可以使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途径控制，该途径的激活导致Cdc2/Cyclin B复合物，G2停滞和免受TMZ毒性的保护。我们最近发现的证据表明，涉及p38应激激酶的第二个独立途径也可能控制TMZ诱导的G2停滞，进而控制TMZ敏感性/抗性。尽管它在控制TMZ敏感性/电阻方面具有潜在的重要性，但p38途径激活的激活和后果以及与CHK1途径的相互作用及其与CHK1途径的相互作用以及治疗性操作的潜力仍然不确定。我们假设1）通过DNA不匹配修复诱导的DNA单链破裂在TMZ暴露后激活p38途径，2）DNA损伤传感器C-ABL，53BP1，ATM和/或ATR链路链路MMR链接MMR诱导的DNA诱导的DNA损害对p38激活的DNA损害，对p38施加了p38的cd-cdiription cdiripiation cdmz- cdiripiation cdiripiation cdiriation cdiripiation cdiripiation cdiriation cdiripiation cdiripiation cdiriation cdiriation cdiripiation cdmz- B和/或Cdc25c，以及Cdc2-Cyclin B复合物，4）P38通过对P53-和P21依赖性CDC2的影响来维持TMZ诱导的G2停滞 激活，以及5）抑制p38和CHK1途径将在体外和体内添加或协同使神经胶质瘤细胞对TMZ敏感。这些研究的结果预计将更好地理解TMZ诱导的G2检查点，并鉴定TMZ诱导的G2检查点及其抗TMZ耐药性的方法，可以选择性地反转神经胶质瘤。