A new mammalian DNA topoisomerase I poison Hoechst 33342: cytotoxicity and drug resistance in human cell cultures.
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.
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway 08854-5635.
A Y
AY
Chen
C
C
Yu
A
A
Bodley
L F
LF
Peng
L F
LF
Liu
D001562:Benzimidazoles / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004351:Drug Resistance; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001562:Benzimidazoles; D005456:Fluorescent Dyes; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin