Catalytic inhibition of human DNA topoisomerase IIalpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum).
St. John's wort (Hypericum perforatum) is the most widely used herbal medicine for the treatment of depression. However, concerns have arisen about the potential of its interaction with other drugs due to the induction of cytochrome P450 isozymes 1A2 and 3A4 by the components hypericin and hyperforin, 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. Preliminary findings that hypericin inhibited the DNA relaxation activity of topoisomerase IIalpha (topo II; EC 5.99.1.3) led us to investigate the mechanism of enzyme inhibition. Rather than stabilizing the enzyme in covalent complexes with DNA (cleavage complexes), hypericin inhibited the enzyme prior to DNA cleavage. In vitro assays indicate that hypericin is a potent antagonist of cleavage complex stabilization by the chemotherapeutics etoposide and amsacrine. This antagonism appears to be due to the ability of hypericin to intercalate 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-resistant HL-60 leukemia cell lines. Moreover, hypericin was incapable of stimulating DNA damage-responsive gene promoters that are activated by etoposide. As with the in vitro topo II assay, antagonism of DNA damage stimulated by 30 microM etoposide was evident in leukemia cells pretreated with 5 microM hypericin. Since many cancer patients experience clinical depression and concomitantly self-medicate with herbal remedies, extracts of St. John's wort should be investigated further for their potential to antagonize topo II-directed chemotherapy regimens.
Peebles
K A
KA
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
Baker
R K
RK
Kurz
E U
EU
Schneider
B J
BJ
Kroll
D J
DJ
D000873:Anthracenes; D000951:Antigens, Neoplasm; D002384:Catalysis; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008517:Phytotherapy; D010946:Plants, Medicinal; D059005:Topoisomerase II Inhibitors
D000873:Anthracenes; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors; D010569:Perylene; C004965:hypericin; D004250:DNA Topoisomerases, Type II