Abrogation of the Chk1-mediated G2 Checkpoint Pathway Potentiates Temozolomide-induced Toxicity in a p53-independent Manner in Human Glioblastoma Cells

摘要: Temozolomide (TMZ) produces O(6)-methylguanine in DNA, which turn mispairs with thymine, triggering futile DNA mismatch repair (MMR) and ultimately cell death. We found previously that p53-proficient human glioma cells, TMZ-induced MMR resulted not apoptosis but rather prolonged, p53- p21-associated G(2)-M arrest senescence. Additionally, p53-deficient cells were relatively more TMZ resistant than underwent only transient before death by mitotic catastrophe. These results suggested prolonged might protect from cytotoxicity. In the present study, we therefore focused on mechanism induces whether inhibition of such sensitize to toxicity. U87MG treated associated Chk1 activation phosphorylation both cdc25C cdc2. effects inhibited kinase inhibitor UCN-01. Although itself toxic, UCN-01 increased cytotoxicity 5-fold, primarily inhibiting cellular senescence increasing percentage bypassing undergoing addition enhancing also blocked U87MG-E6 similarly enhanced catastrophe Taken together, these indicate links arrest. Furthermore, cytoprotective G(2) pathway sensitizes may represent a novel, mechanism-based means efficacy p53 wild-type mutant cells.