Open AccessDNA ligase IV is a potential molecular target in ACNU sensitivity
Author(s) -
Kondo Natsuko,
Takahashi Akihisa,
Mori Eiichiro,
Noda Taichi,
Su Xiaoming,
Ohnishi Ken,
McKin Peter J.,
Sakaki Toshisuke,
Nakase Hiroyuki,
Ono Koji,
Ohnishi Takeo
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01591.x
Subject(s) - dna ligase , sensitivity (control systems) , dna , genetics , computational biology , ligase chain reaction , biology , chemistry , microbiology and biotechnology , polymerase chain reaction , gene , engineering , electronic engineering , multiplex polymerase chain reaction
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. ( Cancer Sci 2010)