A DNA topoisomerase II-independent route for novobiocin-mediated resistance to DNA binding agents.
The coumermycin antibiotic novobiocin is currently under investigation as an agent that can modify the toxicity of various anti-cancer drugs, potentially via one of its many pharmacological effects: namely, the interference with type II DNA topoisomerase function. This paper investigates the ability of novobiocin to modify the cellular/nuclear accumulation and toxicity of two types of DNA binding agents (the minor groove ligand Hoechst 33342 and the intercalating anthracycline Adriamycin). We report that novobiocin reduces the cytotoxicity of both agents and that this can be attributed to a reduction in cellular and, consequently, nuclear accumulation of these agents rather than to any effect on cellular export. The antibiotic was also active (at non-toxic concentrations) in delaying the progression of cells into S phase and G2 phase. This potential for novobiocin to effect rescue from toxicity by disturbance of the delivery of a drug to a potentially important intracellular target, together with the provision of an extended period of cellular recovery prior to the commitment of cells to G2 + M phase, should be recognised in the design of combination chemotherapy.
Smith
P J
PJ
Clinical Oncology Radiotherapeutics Unit, Medical Research Council Centre, Cambridge, UK.
Bell
S M
SM
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D005434:Flow Cytometry; D051379:Mice; D009675:Novobiocin / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D001562:Benzimidazoles; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; D004317:Doxorubicin; C017807:bisbenzimide ethoxide trihydrochloride