Inhibition of mitosis and microtubule function through direct tubulin binding by a novel antiproliferative naphthopyran LY290181.
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 cells 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.
Wood
D L
DL
Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
Panda
D
D
Wiernicki
T R
TR
Wilson
L
L
Jordan
M A
MA
Singh
J P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D016195:G2 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008677:Metaphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology*; D011714:Pyrans / Q000378:metabolism* / Q000494:pharmacology*; D011817:Rabbits; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C094200:LY 290181; D009281:Naphthalenes; D011714:Pyrans; D014404:Tubulin