期刊
CANCER LETTERS
卷 520, 期 -, 页码 361-373出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.08.006
关键词
DNA repair; DNA damage Response; RAD51 inhibition; Doxorubicin
类别
资金
- Deutsche Forschungsgemeinschaft (DFG Research Training Group (RTG)) [270650915/GRK2158]
- Dusseldorf School of Oncology (DSO)
- DFG Research Training Group (RTG) [GRK 2578]
The RAD51 inhibitor B02 synergistically increases Doxo-induced cytotoxicity through various mechanisms, including G2/M arrest, mitochondrial damage, and caspase-driven apoptosis. B02 also promotes the cytotoxicity of oxaliplatin and 5-FU, and enhances Doxo-induced cytotoxicity in MMR-proficient colon and mammary carcinoma cells. Pharmacological inhibition of RAD51 is suggested to enhance the cytotoxic effectiveness of conventional anticancer drugs in different tumor entities.
The anthracycline derivative doxorubicin (Doxo) induces DNA double-strand breaks (DSBs) by inhibition of DNA topoisomerase type II. Defective mismatch repair (MMR) contributes to Doxo resistance and has been reported for colon and mammary carcinomas. Here, we investigated the outcome of pharmacological inhibition of various DNA repair-related mechanisms on Doxo-induced cytotoxicity employing MMR-deficient HCT-116 colon carci-noma cells. Out of different inhibitors tested (i.e. HDACi, PARPi, MRE11i, RAD52i, RAD51i), we identified the RAD51-inhibitor B02 as the most powerful compound to synergistically increase Doxo-induced cytotoxicity. B02-mediated synergism rests on pleiotropic mechanisms, including pronounced G2/M arrest, damage to mito-chondria and caspase-driven apoptosis. Of note, B02 also promotes the cytotoxicity of oxaliplatin and 5-fluorur-acil (5-FU) in HCT-116 cells and, furthermore, also increases Doxo-induced cytotoxicity in MMR-proficient colon and mammary carcinoma cells. Summarizing, pharmacological inhibition of RAD51 is suggested to synergisti-cally increase the cytotoxic efficacy of various types of conventional anticancer drugs in different tumor entities. Hence, pre-clinical in vivo studies are preferable to determine the therapeutic window of B02 in a clinically oriented therapeutic regimen.
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