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Kinetic suppression of microtubule dynamic instability by griseofulvin: Implications for its possible use in the treatment of cancer

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Title Kinetic suppression of microtubule dynamic instability by griseofulvin: Implications for its possible use in the treatment of cancer
 
Creator PANDA, D
RATHINASAMY, K
SANTRA, MK
WILSON, L
 
Subject tubulin
polymerization
binding
invitro
taxol
stabilization
vinblastine
inhibition
mechanism
protein
cancer chemotherapy
mitosis
 
Description The antifungal drug griseofulvin inhibits mitosis strongly in fungal cells and weakly in mammalian cells by affecting mitotic spindle microtubule (MT) function. Griseofulvin also blocks cell-cycle progression at G(2)/M and induces apoptosis in human tumor cell lines. Despite extensive study, the mechanism by which the drug inhibits mitosis in human cells remains unclear. Here, we analyzed the ability of griseofulvin to inhibit cell proliferation and mitosis and to affect MT polymerization and organization in HeLa cells together with its ability to affect MT polymerization and dynamic instability in vitro. Griseofulvin inhibited cell-cycle progression at prometaphase/anaphase of mitosis in parallel with its ability to inhibit cell proliferation. At its mitotic IC50 of 20 mu M, spindles in blocked cells displayed nearly normal quantities of MTs and MT organization similar to spindles blocked by more powerful MT-targeted drugs. Similar to previously published data, we found that very high concentrations of griseofulvin (> 100 mu M) were required to inhibit MT polymerization in vitro. However, much lower drug concentrations (1-20 mu M) strongly suppressed the dynamic instability behavior of the MTs. We suggest that the primary mechanism by which griseofulvin inhibits mitosis in human cells is by suppressing spindle MT dynamics in a manner qualitatively similar to that of much more powerful antimitotic drugs, including the vinca alkaloids and the taxanes. in view of griseofulvin's lack of significant toxicity in humans, we further suggest that it could be useful as an adjuvant in combination with more powerful drugs for the treatment of cancer.
 
Publisher NATL ACAD SCIENCES
 
Date 2011-08-19T00:56:40Z
2011-12-26T12:55:58Z
2011-12-27T05:43:45Z
2011-08-19T00:56:40Z
2011-12-26T12:55:58Z
2011-12-27T05:43:45Z
2005
 
Type Article
 
Identifier PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 102(28), 9878-9883
0027-8424
http://dx.doi.org/10.1073/pnas.0501821102
http://dspace.library.iitb.ac.in/xmlui/handle/10054/10171
http://hdl.handle.net/10054/10171
 
Language en