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Inhibition of human topoisomerase II by anti-neoplastic benzazolo[3,2-a]quinolinium chlorides

Authors
  • Vivas-Mejía, Pablo E.1, 2
  • Cox, Osvaldo1
  • González, Fernando A.1, 2
  • 1 University of Puerto Rico, Department of Chemistry, Rio Piedras Campus, San Juan, Puerto Rico , San Juan
  • 2 University of Puerto Rico, Biotesting Center, Rio Piedras Campus, San Juan, Puerto Rico , San Juan
Type
Published Article
Journal
Molecular and Cellular Biochemistry
Publisher
Springer-Verlag
Publication Date
Jan 01, 1998
Volume
178
Issue
1-2
Pages
203–212
Identifiers
DOI: 10.1023/A:1006847615575
Source
Springer Nature
Keywords
License
Yellow

Abstract

Previously we reported [20] that there is no correlation between the cytotoxic activity of four new structural analogs of the antitumor DNA intercalator 3-nitrobenzothiazolo[3,2-a]quinolinium chloride (NBQ-2) and their interaction with DNA. In the present study, we present evidence suggesting that the molecular basis for the anti-proliferative activity of these drugs is the inhibition of topoisomerase II. The NBQ-2 derivatives inhibited the relaxation of supercoiled DNA plasmid pRYG mediated by purified human topoisomerase II. Inhibition of the decatenation of kinetoplast DNA mediated by partially purified topoisomerase II extracted from the human histiocytic lymphoma U937 (a cell line previously shown to be sensitive to the drugs) was also caused by these drugs. The potency of the benzazolo[3,2-a]quinolinium drugs against topoisomerase II in vitro was the following: 7-(1-propenyl)-3-nitrobenzimidazolo[3,2-a]quinolinium chloride (NBQ-59) > 4-chlorobenzothiazolo[3,2-a]quinolinium chloride (NBQ-76) > 7-ethyl-3-nitrobenzimidazolo[3,2-a]quinolinium chloride (NBQ-48) > 7-benzyl-3-nitrobenzimidazolol[3,2-a]quinolinium chloride (NBQ-38). This rank of potency for topoisomerase II inhibition correlated very well with the cytotoxicity elicited by these drugs. Furthermore, significant levels of topoisomerase II/DNA cleavage complex induced by these drugs in vivo were detected when U937 cells were treated with NBQ-59 and NBQ-76 whereas NBQ-38 and NBQ-38 and NBQ-48 produced negligible amounts of the cleavage complex. Our results strongly suggest that topoisomerase II is the major cellular target of this family of compounds.

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