title: DNA ligase IV is a potential molecular target in ACNU sensitivity.
abstract: Nimustine (ACNU) is a chloroethylating agent which was the most active chemotherapy agent used for patients with high-grade gliomas until the introduction of temozolomide, which became the standard of care for patients with newly diagnosed glioblastomas in Japan. Since temozolomide was established as the standard first-line therapy for glioblastoma multiforme (GBM), ACNU has been employed as a salvage chemotherapy agent for recurrent GBM in combination with other drugs. The acting molecular mechanism in ACNU has yet to be elucidated. ACNU is a cross-linking agent which induces DNA double-strand breaks (DSBs). The work described here was intended to clarify details in repair pathways which are active in the repair of DNA DSBs induced by ACNU. DSBs are repaired through the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. Cultured mouse embryonic fibroblasts were used which have deficiencies in DNA DSB repair genes which are involved in HR repair (X-ray repair cross-complementing group 2 [XRCC2] and radiation sensitive mutant 54 [Rad54]), and in NHEJ repair (DNA ligase IV [Lig4]). Cellular sensitivity to ACNU treatment was evaluated with colony forming assays. The most effective molecular target which correlated with ACNU cell sensitivity was Lig4. In addition, it was found that Lig4 small-interference RNA (siRNA) efficiently enhanced cell lethality which was induced by ACNU in human glioblastoma A172 cells. These findings suggest that the down-regulation of Lig4 might provide a useful tool which can be used to increase cell sensitivity in response to ACNU chemotherapy.
authors.affiliation: Department of Biology, School of Medicine, Nara Medical University, Nara, 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: Taichi
authors.initials: T
authors.lastname: Noda
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Su
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: Koji
authors.initials: K
authors.lastname: Ono
authors.forename: Takeo
authors.initials: T
authors.lastname: Ohnishi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004260:DNA Repair; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D051379:Mice; D015376:Nimustine / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C000607893:LIG4 protein, human; D009687:Nuclear Proteins; D015376:Nimustine; D004265:DNA Helicases; C103534:Rad54l protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP