Targeting RAD51: eine Verstärkung der Alkylanzien-induzierten Zytotoxizität von Glioblastomzellen durch Hemmung der Homologen Rekombinationsreparatur
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Abstract
Glioblastoma is a tumor disease of the central nervous system with mostly fatal outcome. The current chemotherapy based on alkylating agents does not offer a satisfactory clinical benefit for glioblastoma patients. Despite a radical treatment regimen, the median survival of these patients is below 15 months. In order to improve the response to the applied thera-py, combination and targeted treatment strategies become increasingly important.
In the present study, two new combined treatment approaches were used to sensitize glio-blastoma cells to the clinically relevant cytostatic agents temozolomide (TMZ) and lomustin (CCNU).
In the first approach, the antimalarial drug artesunat (ART) was combined with the alkylating agent TMZ, the gold standard of glioblastoma therapy. The induced cytotoxicity could be attributed to an increase of DNA double-strand breaks (DSBs). Simultaneously, the inhibition of homologous recombination repair (HRR), which prevents from or eliminates DSBs, has also been demonstrated. Furthermore, ART reduced TMZ-induced senescence, possibly also contributing to the enhancement of cytotoxicity. Investigations in the nude mouse model with subcutaneously injected glioblastoma cells showed a good tolerability of both drugs and significant improvement of TMZ-based chemotherapy concomitant with ART.
In a second approach, a targeted treatment strategy was achieved through the use of phar-macological inhibitors. RAD51, the key enzyme of HRR, was inhibited by B02 or RI-1, whereas MRN complex, which is involved in the DNA damage response, was silenced by mirin, an in-hibitor of MRE11. A comparative study analyzing the reinforcement of CCNU-induced cytox-icity in glioblastoma cells showed that the RAD51 inhibitor RI-1 is the most promising one of these inhibitors. In combination with CCNU, RI-1 prevented the repair of CCNU-induced DSBs. In addition to enhancing the clastogenicity of CCNU, combined treatment also led to an increase in cell death. In the xenograft mouse model, combination therapy with CCNU followed by RI-1 treatment was well tolerated and prevented tumor growth. In some ani-mals a complete regression of tumors was observed.
Based on the preclinical data obtained in this work, the combination treatments offer a promising basis for clinical trials, which may finally lead to improvements in glioblastoma therapy.