Targeting homologous recombination in glioma chemotherapy

Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First and second line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNUs) lomustine, nimustine, fotemustine and carmustine. These agents target the tumor DNA, forming O6-chloroethylguanine adducts and secondary DNA interstrand crosslinks (ICLs). These crosslinks are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacological inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggests that pharmacological inhibition of HR, e.g. by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs.

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