Antihelicase action of DNA-binding anticancer agents: relationship to guanosine-cytidine intercalator binding.
DNA-binding antibiotics such as intercalators, narrow groove binders, and other substances modify duplex DNA, making it an altered substrate for DNA helicases. The intercalators daunorubicin, actinomycin D, echinomycin, and elsamicin, the narrow groove binders distamycin and mithramycin, and the plant toxin teniposide, each representing a different chemical class, block SV40 large T antigen DNA helicase action with IC50 values ranging from 4 x 10(-8) to 2 x 10(-6) M. A partially purified human HeLa cell DNA helicase is also potently blocked by daunorubicin, distamycin, and teniposide. Because eukaryotic cells contain helicases of varying abundance, specificity, and type, this site of action for DNA-binding antibiotics may help explain antibiotic potency and specificity for DNA or RNA inhibition. The antihelicase effect of the antibiotic-double-stranded DNA complex may be central to the anticancer activities of these substances. An additional interesting correlation is the antihelicase action of DNA-intercalating antibiotics and their DNA-binding preference for G-C base pair sites. The G-C base pair binding preference of the intercalating antibiotics may result from evolutionary selection because of the higher G-C binding stability, compared with A-T binding stability. The combination of the higher base pair stability at G-C regions and increased duplex DNA stability induced by intercalating antibiotic yields a total additive stability of the intercalator-G-C base pair complex that resists helicase action.
Bachur
N R
NR
Department of Medicine, University of Maryland School of Medicine, Baltimore.
Johnson
R
R
Yu
F
F
Hickey
R
R
Applegren
N
N
Malkas
L
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D000952:Antigens, Polyomavirus Transforming / Q000187:drug effects; D001483:Base Sequence; D002240:Carbohydrate Sequence; D003562:Cytidine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006151:Guanosine / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000952:Antigens, Polyomavirus Transforming; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D009097:Multienzyme Complexes; D006151:Guanosine; D003562:Cytidine; D004247:DNA; D004265:DNA Helicases