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Please use this identifier to cite or link to this item: http://dspace.library.iitb.ac.in/jspui/handle/10054/3724

Title: Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin
Authors: GUPTA, K
BISHOP, J
PECK, A
BROWN, J
WILSON, L
PANDA, D
Keywords: beta-tubulin
aspergillus-nidulans
saccharomyces-cerevisiae
anthelmintic benzimidazoles
kinetic stabilization
directed mutagenesis
sulfhydryl-groups
vinca alkaloids
budding yeast
colchicine
Issue Date: 2004
Publisher: AMER CHEMICAL SOC
Citation: BIOCHEMISTRY, 43(21), 6645-6655
Abstract: The antifungal agent benomyl [methyl-l-(butylcarbamoyl)-2-benzimidazolecarbamate] is used throughout the world against a wide range of agricultural fungal diseases. In this paper, we investigated the interaction of benomyl with mammalian brain tubulin and microtubules. Using the hydrophobic fluorescent probe 1-anilinonaphthalene-8-sulfonic acid, benomyl was found to bind to brain tubulin with a dissociation constant of 11.9 +/- 1.2 muM. Further, benomyl bound to at a novel site, distinct from the well-characterized colchicine and vinblastine binding sites. Benomyl altered the far-UV circular dichroism spectrum of tubulin and reduced the accessibility of its cysteine residues to modification by 5,5'-dithiobis-2-nitrobenzoic acid, indicating that benomyl binding to tubulin induces a conformational change in the tubulin. Benomyl inhibited the polymerization of brain tubulin into microtubules, with 50% inhibition occurring at a concentration of 70-75 muM. Furthermore, it strongly suppressed the dynamic instability behavior of individual brain microtubules in vitro as determined by video microscopy. It reduced the growing and shortening rates of the microtubules but did not alter the catastrophe or rescue frequencies. The unexpected potency of benomyl against mammalian microtubule polymerization and dynamics prompted us to investigate the effects of benomyl on HeLa cell proliferation and mitosis. Benomyl inhibited proliferation of the cells with an IC50 of 5 muM, and it blocked mitotic spindle function by perturbing microtubule and chromosome organization. The greater than expected actions of benomyl on mammalian microtubules and mitosis together with its relatively low toxicity suggest that it might be useful as an adjuvant in cancer chemotherapy.
URI: http://dx.doi.org/10.1021/bi036112v
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3724
http://hdl.handle.net/10054/3724
ISSN: 0006-2960
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