title: DNA ligase IV as a new molecular target for temozolomide.
abstract: Temozolomide (TMZ) is a methylating agent used in chemotherapy against glioblastoma. This work was designed to clarify details in repair pathways acting to remove DNA double-strand breaks (DSBs) induced by TMZ. Cultured mouse embryonic fibroblasts were used which were deficient in DSB repair genes such as homologous recombination repair-related genes X-ray repair cross-complementing group 2 (XRCC2)and radiation sensitive mutant54 (Rad54), non-homologous end joining repair-related gene DNAligase IV (Lig4). Cell sensitivity to drug treatments was assessed using colony forming assays. The most effective molecular target which was correlated with TMZ cell sensitivity was Lig4. In addition, it was found that small interference RNAs (siRNA) for Lig4 efficiently enhanced cell lethality induced by TMZ in human glioblastoma A172 cells. These findings suggest that down regulation of Lig4 might provide a useful tool for cell sensitization during TMZ chemotherapy.
authors.affiliation: Department of Biology, Nara Medical University, Shijo-cho, Kashihara, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kondo
authors.forename: Akihisa
authors.initials: A
authors.lastname: Takahashi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Mori
authors.forename: Ken
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.forename: Toshisuke
authors.initials: T
authors.lastname: Sakaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakase
authors.forename: Takeo
authors.initials: T
authors.lastname: Ohnishi
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; C000607893:LIG4 protein, human; D003606:Dacarbazine; D011088:DNA Ligases; D000072481:DNA Ligase ATP; D000077204:Temozolomide