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Suppression of microtubule dynamics by benomyl decreases tension across kinetochore pairs and induces apoptosis in cancer cells

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Title Suppression of microtubule dynamics by benomyl decreases tension across kinetochore pairs and induces apoptosis in cancer cells
 
Creator RATHINASAMY, K
PANDA, D
 
Subject directional instability
chromosome congression
spindle checkpoint
anticancer drugs
mitotic spindle
protein-kinase
anaphase onset
attachment
binding
bcl-2
apoptosis
benomyl
bcl2
centrosomes
microtubule dynamics
 
Description We found that benomyl, a benzimidazole fungicide, strongly suppressed the reassembly of cold-depolymerized spindle microtubules in HeLa cells. Benomyl perturbed microtubule-kinetochore attachment and chromosome alignment at the metaphase plate. Benomyl also significantly decreased the distance between the sister kinetochore pairs in metaphase cells and increased the level of the checkpoint protein BubR1 at the kinetochore region, indicating that benomyl caused loss of tension across the kinetochores. In addition, benomyl decreased the intercentrosomal distance in mitotic HeLa cells and blocked the cells at mitosis. Further, we analyzed the effects of benomyl on the signal transduction pathways in relation to mitotic block, bcl2 phosphorylation and induction of apoptosis. The results suggest that benomyl causes loss of tension across the kinetochores, blocks the cell cycle progression at mitosis and subsequently, induces apoptosis through the bcl2-bax pathway in a manner qualitatively similar to the powerful microtubule targeted anticancer drugs like the vinca alkaloids and paclitaxel. Considering the very high toxicity of the potent anticancer drugs and the low toxicity of benomyl in humans, we suggest that benomyl could be useful as an adjuvant in combination with the powerful anticancer drugs in cancer therapy.
 
Publisher BLACKWELL PUBLISHING
 
Date 2011-07-19T04:38:16Z
2011-12-26T12:51:00Z
2011-12-27T05:37:17Z
2011-07-19T04:38:16Z
2011-12-26T12:51:00Z
2011-12-27T05:37:17Z
2006
 
Type Article
 
Identifier FEBS JOURNAL, 273(17), 4114-4128
1742-464X
http://dx.doi.org/10.1111/j.1742-4658.2006.05413.x
http://dspace.library.iitb.ac.in/xmlui/handle/10054/5176
http://hdl.handle.net/10054/5176
 
Language en