Inhibition of mitosis and microtubule function through direct tubulin binding by a novel antiproliferative naphthopyran LY290181

Dan L. Wood, Dulal Panda, Todd R. Wiernicki, Leslie Wilson, Mary Ann Jordan, Jai Pal Singh

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The mechanism of action of a novel antiproliferative compound LY290181 [2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile] was characterized. LY290181 is a potent inhibitor of cell proliferation, producing 50% inhibition of vascular smooth muscle, endothelial, Chinese hamster ovary, HeLa, and human erythroleukemia cells at concentrations of 8- 40 nM. Cell cycle analysis showed that LY290181 caused accumulation of smooth muscle cells at the G2/M phase and induced mitotic arrest in Chinese hamster ovary cells and HeLa cells. At low concentrations (3-30 nM), LY290181 blocked transition of celts from metaphase to anaphase and disrupted mitotic spindle organization. At high concentrations (≤100 nM), LY290181 produced a concentration-dependent loss of cytoplasmic and spindle microtubules. LY290181 inhibited the polymerization of purified bovine brain microtubule protein into microtubules, and it depolymerized preformed microtubules. Using tubulin-1-anilino-8-naphthalene sulfonate complex fluorescence, we have shown that LY290181 directly interacted with tubulin in a unique manner. These studies show that LY290181 induces cell growth arrest in prometaphase/metaphase, and tubulin appears to be its molecular target.

Original languageEnglish (US)
Pages (from-to)437-444
Number of pages8
JournalMolecular Pharmacology
Volume52
Issue number3
DOIs
StatePublished - Sep 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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