A new mammalian DNA topoisomerase I poison Hoechst 33342

Cytotoxicity and drug resistance in human cell cultures

A. Y. Chen, C. Yu, A. Bodley, L. F. Peng, Leroy-Fong Liu

Research output: Contribution to journalArticle

148 Citations (Scopus)

Abstract

Hoechst dye 33342 (Ho33342), like many other DNA minor groove binding ligands and its parent compound Hoechst dye 33258 (Ho33258), nonspecifically inhibits the catalytic activities of many DNA enzymes. However, both Ho33258 and Ho33342 also specifically interrupt the breakage/reunion reaction of mammalian DNA topoisomerase I by trapping reversible topoisomerase I cleavable complexes. The enhanced membrane permeability of Ho33342 over its parent compound Ho33258 has allowed studies of the cellular action of Ho33342. Our results suggest that Ho33342 also traps topoisomerase I but not topoisomerase II into reversible cleavable complexes in human KB cells. Although Ho33342 shares a similar mechanism of action with camptothecin, a prototypic topoisomerase I poison, in trapping topoisomerase I cleavable complexes, Ho33342 differs from camptothecin in its effect on drug-resistant cells. Different from camptothecin, Ho33342 was shown to be about 200-fold less cytotoxic in MDR1-overexpressing human KB V1 cells relative to parental human KB 3-1 cells. Ho33342 is only 5-fold less cytotoxic for camptothecin- resistant CPT-K5 cells, which expresses a highly camptothecin-resistant from of topoisomerase I, than for the wild type human lymphoblast RPMI 8402 cells. Our studies suggest a potential use of Hoechst 33342 as a new topoisomerase I poison in antitumor chemotherapy.

Original languageEnglish
Pages (from-to)1332-1337
Number of pages6
JournalCancer Research
Volume53
Issue number6
Publication statusPublished - 1993
Externally publishedYes

Fingerprint

Type I DNA Topoisomerase
Poisons
Drug Resistance
Coloring Agents
Cell Culture Techniques
Camptothecin
Bisbenzimidazole
KB Cells
HOE 33342
Reunion
Type II DNA Topoisomerase
DNA
Permeability

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A new mammalian DNA topoisomerase I poison Hoechst 33342 : Cytotoxicity and drug resistance in human cell cultures. / Chen, A. Y.; Yu, C.; Bodley, A.; Peng, L. F.; Liu, Leroy-Fong.

In: Cancer Research, Vol. 53, No. 6, 1993, p. 1332-1337.

Research output: Contribution to journalArticle

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