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Microtubules as a target for anticancer drugs
Nature Reviews Cancervolume 4, pages253–265 (2004)Cite this article
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Key Points
Microtubules are highly dynamic cytoskeletal fibres that are composed of tubulin subunits. They show two types of non-equilibrium dynamics — treadmilling and dynamic instability — both of which are crucial to mitosis and cell division.
Dynamic microtubules continue to be one of the most successful cancer chemotherapeutic targets. Many new drugs that target microtubules are in clinical trials and large numbers of microtubule-active compounds are being developed.
Among the most successful microtubule-targeted chemotherapeutic drugs are paclitaxel and theVinca alkaloids, which were previously thought to work through opposite mechanisms. We now recognize that their most potent actions are suppression of microtubule dynamics, rather than increasing or decreasing microtubule-polymer mass.
Microtubule-active drugs generally bind to one of three main classes of sites on tubulin, the paclitaxel site, theVinca domain and the colchicine domain. Drugs that bind to the colchicine domain are undergoing intensive investigation as vascular-targeting agents for cancer therapy.
Development of resistance to microtubule-targeted drugs has several possible causes, some of which might involve changes in microtubule dynamics resulting from altered expression of tubulin isotypes, tubulin mutations, and altered expression or binding of microtubule-regulatory proteins.
Microtubule-targeted drugs can synergize with one another.
Understanding their modes of action might lead to improved dosing regimens and combinations with other microtubule-targeted drugs, as well as combinations with 'molecularly targeted' drugs.
Abstract
Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy. Microtubule-targeted drugs, including paclitaxel andVinca alkaloids, were previously considered to work primarily by increasing or decreasing the cellular microtubule mass. Although these effects might have a role in their chemotherapeutic actions, we now know that at lower concentrations, microtubule-targeted drugs can suppress microtubule dynamics without changing microtubule mass; this action leads to mitotic block and apoptosis. In addition to the expanding array of chemically diverse antimitotic agents, some microtubule-targeted drugs can act as vascular-targeting agents, rapidly depolymerizing microtubules of newly formed vasculature to shut down the blood supply to tumours.
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Acknowledgements
We thank K. Kamath for critical reading of the manuscript. Supported by grants from the National Institutes of Health.
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University of California Santa Barbara, Santa Barbara, 93106, California, USA
Mary Ann Jordan & Leslie Wilson
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Correspondence toMary Ann Jordan.
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The authors receive reasearch money or materials from Eli Lilly company, Pierre Fabre Centre de Recherche, Aventis, Novartis and Eisai Research Institute.
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Jordan, M., Wilson, L. Microtubules as a target for anticancer drugs.Nat Rev Cancer4, 253–265 (2004). https://doi.org/10.1038/nrc1317
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