P38, G2 Arrest, and Temozolomide Resistance in Gliomas

描述（由申请方提供）：本研究的长期目的是通过更好地了解替莫唑胺（TMZ）（一种治疗胶质瘤的重要化疗药物）敏感性/耐药性的基础，改善胶质瘤的治疗。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，G2细胞周期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检查点部分受Chk 1通路控制，其激活导致Cdc 2/细胞周期蛋白B复合物磷酸化、G2阻滞和TMZ毒性保护。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期阻滞，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，以及其与Chk 1通路的相互作用和治疗操作的潜力仍然不确定。我们假设：1）在TMZ暴露后，p38通路通过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、53 BP 1、ATM和/或ATR将MMR诱导的DNA损伤与p38激活连接，3）激活的p38通过抑制Cdc 25 B和/或Cdc 25 C的核活性而有助于TMZ诱导的G2停滞的起始，和Cdc 2-细胞周期蛋白B复合物; 4）p38 通过对p53和p21依赖性Cdc 2的影响，有助于维持TMZ诱导的G2期阻滞 激活，和5）抑制p38和Chk 1途径将在体外和体内使胶质瘤细胞对TMZ增敏或协同增敏。这些研究的结果预计将导致更好地理解TMZ诱导的G2检查点，并确定TMZ诱导的G2检查点，从而TMZ耐药，可以在胶质瘤中选择性逆转的方式。

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.