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.
Bielawski
Krzysztof
K
Department of Medicinal Chemistry and Drug Technology, Medical University of Białystok, Kilińskiego 1, PL 15-089, Poland. kbiel@amb.edu.pl
Wołczyński
Sławomir
S
Bielawska
Anna
A
D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D006801:Humans; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D001562:Benzimidazoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA