DNA ligase IV as a new molecular target for temozolomide.
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.
Kondo
Natsuko
N
Department of Biology, Nara Medical University, Shijo-cho, Kashihara, Japan.
Takahashi
Akihisa
A
Mori
Eiichiro
E
Ohnishi
Ken
K
McKinnon
Peter J
PJ
Sakaki
Toshisuke
T
Nakase
Hiroyuki
H
Ohnishi
Takeo
T
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
D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; C000607893:LIG4 protein, human; D003606:Dacarbazine; D011088:DNA Ligases; D000072481:DNA Ligase ATP; D000077204:Temozolomide