The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding: a possible mechanism for its antiproliferative activity

Lopus, Manu ; Panda, Dulal (2006) The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding: a possible mechanism for its antiproliferative activity FEBS Journal, 273 (10). pp. 2139-2150. ISSN 1742-464X

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Official URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1742-...

Related URL: http://dx.doi.org/10.1111/j.1742-4658.2006.05227.x

Abstract

Sanguinarine has been shown to inhibit proliferation of several types of human cancer cell including multidrug-resistant cells, whereas it has minimal cytotoxicity against normal cells such as neutrophils and keratinocytes. By analyzing the antiproliferative activity of sanguinarine in relation to its effects on mitosis and microtubule assembly, we found that it inhibits cancer cell proliferation by a novel mechanism. It inhibited HeLa cell proliferation with a half-maximal inhibitory concentration of 1.6±0.1μm. In its lower effective inhibitory concentration range, sanguinarine depolymerized microtubules of both interphase and mitotic cells and perturbed chromosome organization in mitotic HeLa cells. At concentrations of 2μm, it induced bundling of interphase microtubules and formation of granular tubulin aggregates. A brief exposure of HeLa cells to sanguinarine caused irreversible depolymerization of the microtubules, inhibited cell proliferation, and induced cell death. However, in contrast with several other microtubule-depolymerizing agents, sanguinarine did not arrest cell cycle progression at mitosis. In vitro, low concentrations of sanguinarine inhibited microtubule assembly. At higher concentrations (>40μm), it altered polymer morphology. Further, it induced aggregation of tubulin in the presence of microtubule-associated proteins. The binding of sanguinarine to tubulin induces conformational changes in tubulin. Together, the results suggest that sanguinarine inhibits cell proliferation at least in part by perturbing microtubule assembly dynamics.

Item Type:Article
Source:Copyright of this article belongs to John Wiley and Sons.
Keywords:Cancer Chemotherapy; Microtubules; Mitosis; Sanguinarine; Tubulin
ID Code:34913
Deposited On:14 Apr 2011 13:47
Last Modified:17 May 2016 17:48

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