title: Xrcc2 deficiency sensitizes cells to apoptosis by MNNG and the alkylating anticancer drugs temozolomide, fotemustine and mafosfamide.
abstract: DNA double-strand breaks (DSBs) are potent killing lesions, and inefficient repair of DSBs does not only lead to cell death but also to genomic instability and tumorigenesis. DSBs are repaired by non-homologous end-joining and homologous recombination (HR). A key player in HR is Xrcc2, a Rad51-like protein. Cells deficient in Xrcc2 are hypersensitive to X-rays and mitomycin C and display increased chromosomal aberration frequencies. In order to elucidate the role of Xrcc2 in resistance to anticancer drugs, we compared Xrcc2 knockout (Xrcc2-/-) mouse embryonic fibroblasts with the corresponding isogenic wild-type and Xrcc2 complemented knockout cells. We show that Xrcc2-/- cells are hypersensitive to the killing effect of the simple methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). They undergo apoptosis after MNNG treatment while necrosis is only marginally enhanced. Complementation of Xrcc2 deficient cells by Xrcc2 cDNA transfection conferred resistance to the cytotoxic and apoptosis-inducing effect of MNNG. The hypersensitivity of Xrcc2-/- cells to MNNG prompted us to investigate their killing and apoptotic response to various methylating, chloroethylating and crosslinking drugs used in anticancer therapy. Xrcc2 deficient cells were found to be hypersensitive to temozolomide, fotemustine and mafosfamide. They were also hypersensitive to cisplatin but not to taxol. The data reveal that Xrcc2 plays a role in the protection against a wide range of anticancer drugs and, therefore, suggest Xrcc2 to be a determinant of anticancer drug resistance. They also indicate that HR is involved in the processing of DNA damage induced by simple alkylating agents.
authors.affiliation: Institute of Toxicology, University of Mainz, Obere Zahlbacher Street 67, D-55131 Mainz, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Tsaryk
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fabian
authors.forename: John
authors.initials: J
authors.lastname: Thacker
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D016685:Mitomycin / Q000494:pharmacology; D009153:Mutagens / Q000633:toxicity*; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D009153:Mutagens; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C113187:XRCC2 protein, human; D008769:Methylnitronitrosoguanidine; D016685:Mitomycin; C048341:mafosfamide; D003606:Dacarbazine; D003520:Cyclophosphamide; C054368:fotemustine; D002945:Cisplatin; D000077204:Temozolomide