Inhibition of DNA topoisomerase I and II, and growth inhibition of MDA-MB-231 human breast cancer cells by bis-benzimidazole derivatives with alkylating moiety.

The purpose of the present study was to identify the cellular processes and targets affected by treatment with bis-benzimidazole derivatives with chloroalkyl and bromoalkyl moieties (1-4) in the estrogen receptor-negative MDA-MB-231 human breast cancer cells. Treatment of the cells revealed that these compounds inhibited DNA synthesis and irreversibly inhibited the proliferative activity of the cells. All drugs 1-4 inhibited relaxation of pBR 322 DNA induced by both topoisomerases, although topoisomerase I was 2- to 9-fold more sensitive than topoisomerase II. This suggests that DNA-binding may be implicated in the cytotoxicity of bis-benzimidazole derivatives with alkylating moiety, possibly by inhibiting interactions between topoisomerases and their DNA targets.