Naslov
Inhibition of the DSB repair protein RAD51 potentiates the cytotoxic efficacy of doxorubicin via promoting apoptosis-related death pathways

Autori
Schürmann, Leonie ; Schumacher, Lena ; Roquette, Katharina ; Brozovic, Anamaria ; Fritz, Gerhard

Izvornik
Cancer letters (0304-3835) 520 (2021); 361-373

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
DNA damage Response ; DNA repair ; Doxorubicin ; RAD51 inhibition

Sažetak
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 carcinoma 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 mitochondria and caspase-driven apoptosis. Of note, B02 also promotes the cytotoxicity of oxaliplatin and 5-fluoruracil (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 synergistically 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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA