The Role of Wild-Type p53 in Cisplatin-Induced Chk2 Phosphorylation and the Inhibition of Platinum Resistance with a Chk2 Inhibitor. (31st October 2010)

• Record Type: Journal Article
• Authors: Liang, Xiaobing; Guo, Yi; Figg, William Douglas; Fojo, Antonio Tito; Mueller, Michael D.; Yu, Jing Jie
• Other Names: Tsakris Athanassios Academic Editor.
• Is Part Of: Chemotherapy research and practice. Volume 2011(2011)
• Publication Date: 2010-10-31
• Subjects: Chemotherapy -- Periodicals; Drug Therapy; Pharmaceutical Preparations; Chemotherapy; Electronic journals; Periodical; Periodicals; Fulltext; Internet Resources; Periodicals; 615.58
• DOI: 10.1155/2011/715469
• Languages: English
• ISSNs: 2090-2107

Abstract

Abstract : The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis, and finally treatment failure. Our research goal is to determine and block the mechanisms of platinum resistance. Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin. These include ATM, p53, and Chk2. The increased Chk2 phosphorylation is modulated by p53 in a wild-type p53 model. Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient) cells doubled the amount of Chk2 phosphorylation 48 hours after cisplatin treatment. p53 knockdown by specific siRNA greatly reduced Chk2 phosphorylation. We conclude that wild-type p53, in response to cisplatin stimulation, plays a role in the upstream regulation of Chk2 phosphorylation at Thr-68. Cells without normal p53 function survive via an alternative pathway in response to the exogenous influence of cisplatin. We strongly suggest that it is very important to include the p53 mutational status in any p53 involved studies due to the functional differentiation of wt p53 and p53 mutant. Inhibition of Chk2 pathway with a Chk2 inhibitor (C3742) increased cisplatin efficacy, especially those with defective p53. Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy.