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Please use this identifier to cite or link to this item: http://dspace.library.iitb.ac.in/jspui/handle/10054/3732

Title: Benomyl and Colchicine Synergistically Inhibit Cell Proliferation and Mitosis: Evidence of Distinct Binding Sites for These Agents in Tubulin
Authors: CLEMENT, MJ
RATHINASAMY, K
ADJADJ, E
TOMA, F
CURMI, PA
PANDA, D
Keywords: anthelmintic benzimidazoles
microtubule dynamics
nmr-spectroscopy
structural basis
brain tubulin
bovine brain
drugs
carbendazim
cancer
polymerization
Issue Date: 2008
Publisher: AMER CHEMICAL SOC
Citation: BIOCHEMISTRY, 47(49), 13016-13025
Abstract: Benomyl, a tubulin-targeted antimitotic antifungal agent, belongs to the benzimidazole group of compounds, which are known to inhibit the binding of colchicine to tubulin. Therefore, benomyl was thought to bind at or near the colchicine-binding site on tubulin. However, recent mutational studies in yeast and fluorescence studies involving competitive binding of benomyl and colchicine on goat brain tubulin suggested that benomyl may bind to tubulin at a site distinct from the colchicine-binding site. We set out to examine whether colchicine and benomyl bind to tubulin at distinct sites using a human cervical cancer (HeLa) cell line with the thinking that these agents should exert either additive or synergistic activity on cell proliferation if their binding sites on tubulin are different. We found that benomyl and colchicine synergistically inhibited the proliferation of HeLa cells and blocked their cell cycle progression at mitosis. The synergistic activity of benomyl and colchicine was also apparent from their strong depolymerizing effects on both the spindle and interphase microtubules when used in combinations, providing further evidence that these agents bind to tubulin at different sites. Using NMR spectroscopy, we finally demonstrated that benomyl and colchicine bind to tubulin at different sites and that the binding of colchicine seems to positively influence the binding of benomyl to tubulin and vice versa. Further, an analysis of the saturation transfer difference NMR data yielded an interesting insight into the colchicine-tubulin interaction. The data presented in this study provided a mechanistic understanding of the synergistic effects of benomyl and colchicine on HeLa cell proliferation.
URI: http://dx.doi.org/10.1021/bi801136q
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3732
http://hdl.handle.net/10054/3732
ISSN: 0006-2960
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