Interaction of DNA intercalator 3-nitrobenzothiazolo (3,2-a)quinolinium with DNA topoisomerases: a possible-mechanism for its biological activity.
There is multiple evidence linking the inhibition of DNA topoisomerases I and II with the cytotoxic effects of antitumor drugs such as camptothecin and the DNA intercalators, 4-(9-acridinylamino)methanesulfon-m-anisidine) (mAMSA) and Adriamycin. We have assessed the effect of the DNA intercalator 3-nitrobenzothiazolo(3,2-a)quinolinium (NBQ) on the DNA topoisomerase I and II activities. NBQ has no effect on the activity of purified topoisomerase I, whereas it induced purified topoisomerase II binding to DNA without inducing DNA scission. Above 30 microM, NBQ stimulated formation of double- and single-strand breaks mediated by topoisomerase II in plasmid DNA. Using the alkaline elution technique we determined that NBQ induced single-strand and DNA-protein-associated breaks in the human promyelocytic leukemia cell line HL-60. At sublethal concentrations (less than or equal to 1 microM), NBQ induce HL-60 cells to differentiate. Topoisomerase II-mediated DNA cleavage induced by mAMSA was substantially reduced in NBQ-differentiated cells. Our data suggest that topoisomerase II could play a major role in the biological activity of NBQ in vivo.
Báez
A
A
Laboratoire de Pharmacologie Moléculaire, Institut Gustave Roussy, Villejuif, France.
Riou
J F
JF
Le Pecq
J B
JB
Riou
G
G
D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000494:pharmacology*; D011806:Quinolinium Compounds / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D007364:Intercalating Agents; D011806:Quinolinium Compounds; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C038668:3-nitrobenzothiazolo(3,2-a)quinolinium; D004247:DNA