Cell cycle checkpoints and their impact on anticancer therapeutic strategies.
Cells contain numerous pathways designed to protect them from the genomic instability or toxicity that can result when their DNA is damaged. The p53 tumor suppressor is particularly important for regulating passage through G1 phase of the cell cycle, while other checkpoint regulators are important for arrest in S and G2 phase. Tumor cells often exhibit defects in these checkpoint proteins, which can lead to hypersensitivity; proteins in this class include ataxia-telangiectasia mutatated (ATM), Meiotic recanbination 11 (Mre11), Nijmegen breakage syndrome 1 (Nbs 1), breast cancer susceptibility genes 1 and 2 (BRCA1), and (BRCA2). Consequently, tumors should be assessed for these specific defects, and specific therapy prescribed that has high probability of inducing response. Tumors defective in p53 are frequently considered resistant to apoptosis, yet this defect also provides an opportunity for targeted therapy. When their DNA is damaged, p53-defective tumor cells preferentially arrest in S or G2 phase where they are susceptible to checkpoint inhibitors such as caffeine and UCN-01. These inhibitors preferentially abrogate cell cycle arrest in p53-defective cells, driving them through a lethal mitosis. Wild type p53 can prevent abrogation of arrest by elevating levels of p21(waf1) and decreasing levels of cyclins A and B. During tumorigenesis, tumor cells frequently loose checkpoint controls and this facilitates the development of the tumor. However, these defects also represent an Achilles heel that can be targeted to improve current therapeutic strategies.
Eastman
Alan
A
Department of Pharmacology, and the Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire 03755, USA. alan.eastman@dartmouth.edu
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D004249:DNA Damage; D016195:G2 Phase; D005786:Gene Expression Regulation; D018816:Genes, cdc; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000628:therapy*; D016196:S Phase; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D016159:Tumor Suppressor Protein p53