Loading...
Please wait, while we are loading the content...
Similar Documents
Abrogation of the Chk 1-mediated G 2 Checkpoint Pathway Potentiates Temozolomide-induced Toxicity in a p 53-independent Manner in Human Glioblastoma Cells 1
| Content Provider | Semantic Scholar |
|---|---|
| Author | Hirose, Yuichi Berger, Mitchel S. Pieper, Russell O. |
| Copyright Year | 2001 |
| Abstract | Temozolomide (TMZ) producesO-methylguanine in DNA, which in turn mispairs with thymine, triggering futile DNA mismatch repair (MMR) and ultimately cell death. We found previously that in p53proficient human glioma cells, TMZ-induced futile DNA MMR resulted not in apoptosis but rather in prolonged, p53and p21-associated G 2-M arrest and senescence. Additionally, p53-deficient cells were relatively more TMZ resistant than p53-deficient glioma cells, which underwent only transient G2-M arrest before death by mitotic catastrophe. These results suggested that prolonged G2-M arrest might protect cells from TMZ-induced cytotoxicity. In the present study, we therefore focused on the mechanism by which TMZ induces G2-M arrest and on whether inhibition of such G2-M arrest might sensitize glioma cells to TMZinduced toxicity. U87MG glioma cells treated with TMZ underwent G2-M arrest associated with Chk1 activation and phosphorylation of both cdc25C and cdc2. These TMZ-induced effects were inhibited by the Chk1 kinase inhibitor UCN-01. Although not in itself toxic, UCN-01 increased the cytotoxicity of TMZ 5-fold, primarily by inhibiting cellular senescence and increasing the percentage of cells bypassing G 2-M arrest and undergoing mitotic catastrophe. In addition to enhancing TMZ-induced cytotoxicity in p53-proficient cells, UCN-01 also blocked TMZ-induced Chk1 activation and transient G2-M arrest in p53-deficient U87MG-E6 cells and similarly enhanced TMZ-induced mitotic catastrophe and cell death. Taken together, these results indicate that Chk1 links TMZ-induced MMR to G 2-M arrest. Furthermore, inhibition of the cytoprotective G 2 arrest pathway sensitizes cells to TMZ-induced cytotoxicity and may represent a novel, mechanism-based means of increasing TMZ efficacy in both p53 wild-type and p53 mutant glioma cells. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/61/15/5843.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
