Catalytic inhibition of human DNA topoisomerase II alpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum)

Citation
Ka. Peebles et al., Catalytic inhibition of human DNA topoisomerase II alpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum), BIOCH PHARM, 62(8), 2001, pp. 1059-1070
Citations number
44
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
00062952 → ACNP
Volume
62
Issue
8
Year of publication
2001
Pages
1059 - 1070
Database
ISI
SICI code
0006-2952(20011015)62:8<1059:CIOHDT>2.0.ZU;2-S
Abstract
St. John's wort (Hypericum perforation) is the most widely used herbal medi cine for the treatment of depression. However, concerns have arisen about t he potential of its interaction with other drugs due to the induction of cy tochrome P450 isozymes 1A2 and 3A4 by the components hypericin and hyperfor in, respectively. Structurally similar natural products are often employed as antitumor agents due to their action as inhibitors of DNA topoisomerases , nuclear enzymes that modify DNA during cellular proliferation. Preliminar y findings that hypericin inhibited the DNA relaxation activity of topoisom erase II (topo II; EC 5.99.1.3) led us to investigate the mechanism of enzy me inhibition. Rather than stabilizing the enzyme in covalent complexes wit h DNA (cleavage complexes), hypericin inhibited the enzyme prior to DNA cle avage. In vitro assays indicate that hypericin is a potent antagonist of cl eavage complex stabilization by the chemotherapeutics. etoposide and amsacr ine. This antagonism appears to be due to the ability of hypericin to inter calate or distort DNA structure, thereby precluding topo II binding and/or DNA cleavage. Supporting its non-DNA damaging, catalytic inhibition of topo II, hypericin was shown to be equitoxic to both wild-type and amsacrine-re sistant HL-60 leukemia cell lines. Moreover. hypericin was incapable of sti mulating DNA damage-responsive gene promoters that are activated by etoposi de. As with the in vitro topo II assay, antagonism of DNA damage stimulated by 30 muM etoposide was evident in leukemia cells pretreated with 5 muM hy pericin. Since many cancer patients experience clinical depression and conc omitantly self-medicate with herbal remedies, extracts of St. John's wort s hould be investigated further for their potential to antagonize topo II-dir ected chemotherapy regimens. (C) 2001 Elsevier Science Inc. All rights rese rved.