Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives - Eleutherin, alpha lapachone, and beta lapachone

Citation
P. Krishnan et Kf. Bastow, Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives - Eleutherin, alpha lapachone, and beta lapachone, BIOCH PHARM, 60(9), 2000, pp. 1367-1379
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
60
Issue
9
Year of publication
2000
Pages
1367 - 1379
Database
ISI
SICI code
0006-2952(20001101)60:9<1367:NMODTI>2.0.ZU;2-3
Abstract
Pyranonaphthoquinones have diverse biological activities against Gram posit ive bacteria, fungi and mycoplasms, and, recently, there has also been an i ncreasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its structural isomer, alpha lapachone (compound 3). The mechanism of topoisom erase II inhibition by the three derivatives was examined systematically wi th respect to the steps of the catalytic cycle of the enzyme. Etoposide, th e prototypical enzyme poison, was used as a control and in combination with compounds 1-3 to localize their mechanism of action. The study revealed th at eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by indu cing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II , compound 1 merely slowed the catalytic cycle of the enzyme. alpha Lapacho ne (3), on the other hand, inhibited initial non-covalent binding of topois omerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from D NA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The div erse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoq uinone derivatives reveal novel ways to target the enzyme with potential fo r anti cancer drug design. (C) 2000 Elsevier Science Inc.