Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse.

ABSTRACT: The therapeutic efficacy of the anticancer drug cisplatin is limited by acquired drug resistance. Cisplatin forms DNA crosslinks, that, if not removed, lead to replication stress. Due to this, the DNA damage response (DDR) gets activated regulating cell cycle arrest, DNA repair, cell death or survival. This makes DDR components promising targets for the development of new therapeutic approaches aiming to overcome acquired drug resistance. To this end, cisplatin-resistant bladder cancer cells were analyzed regarding their sensitivity to combination treatments with selected pharmacological DDR inhibitors. Synergistic cytolethal effects were achieved after combined treatment with low to moderate doses of the non-genotoxic RAD51-inhibitor (RAD51_i) B02 and CHK1-inhibitor (CHK1_i<

SUBMITTER: Mann J 

PROVIDER: S-EPMC11578078 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature