Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects bytrapping enzyme-DNA cleavage complexes

Citation
Lh. Meng et al., Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects bytrapping enzyme-DNA cleavage complexes, BIOCH PHARM, 62(6), 2001, pp. 733-741
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
6
Year of publication
2001
Pages
733 - 741
Database
ISI
SICI code
0006-2952(20010915)62:6<733:SANDTI>2.0.ZU;2-F
Abstract
Salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, is a novel anticancer drug candidate. The compound has significa nt in vitro and in vivo activity against malignant tumor cells and xenograf ts, especially some human solid tumor models. This anticancer activity of s alvicine is associated with its ability to induce tumor cell apoptosis. Sal vicine was also found to have a profound cytotoxic effect on multidrug-resi stant (MDR) cell lines by down-regulating the expression of MDR-1 mRNA of M DR cells. Salvicine acted as a topoisomerase II (Topo IT) poison through it s marked enhancement effect on Topo H-mediated DNA double-strand breaks as observed in the DNA cleavage assay. Strong inhibitory activity of salvicine against Topo II was observed in a kDNA decatenation assay, with an approxi mate ic., value of 3 muM. A similar result was obtained by a Topo If-mediat ed supercoiled DNA relaxation assay. In contrast, no inhibitory activity wa s observed against the catalytic activity of Topo I. When the effects of sa lvicine on individual steps of the catalytic cycle of Topo II were dissecte d, it was found that the mechanism by which salvicine inactivates Topo II i s different from that by other anti-Topo II agents. Salvicine greatly promo ted Topo II-DNA binding and inhibited pre- and post-strand Topo II-mediated DNA religation without interference with the forward cleavage steps. In ad dition, salvicine was not a DNA intercalative agent, as demonstrated by DNA unwinding assays. The results of this study indicate that the inhibitory a ctivity of salvicine against Topo II was derived from its ability to stabil ize DNA strand breaks through interactions with the enzyme alone or with th e DNA-enzyme complex. It is therefore postulated that salvicine acts on Top o by trapping the DNA-Topo II complex, which in turn produces anticancer ef fects. (C) 2001 Elsevier Science Inc. All rights reserved.