TAILIEUCHUNG - Báo cáo khoa học: Suppression of microtubule dynamics by benomyl decreases tension across kinetochore pairs and induces apoptosis in cancer cells

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 kineto-chores | ễFEBS Journal Suppression of microtubule dynamics by benomyl decreases tension across kinetochore pairs and induces apoptosis in cancer cells K. Rathinasamy and D. Panda Schoolof Biosciences and Bioengineering Indian Institute of Technology Bombay Mumbai India Keywords apoptosis benomyl bcl2 centrosomes microtubule dynamics Correspondence D. Panda School of Biosciences and Bioengineering Indian Institute of Technology Bombay Powai Mumbai 400 076 India Fax 91 22 257 23480 Tel 91 22 257 67838 E-mail panda@ Received 9 May 2006 revised 27 June 2006 accepted 11 July 2006 doi 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 kineto-chores. 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. Benomyl is a benzimidazole fungicide that is widely

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