tailieunhanh - Báo cáo khoa học: The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding A possible mechanism for its antiproliferative activity Manu Lopus and Dulal Panda

Sanguinarine has been shown to inhibit proliferation of several types of human cancer cell including multidrug-resistant cells, whereas it has min-imal cytotoxicity against normal cells such as neutrophils and keratino-cytes. 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. | ềFEBS Journal The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding A possible mechanism for its antiproliferative activity Manu Lopus and Dulal Panda Schoolof Biosciences and Bioengineering Indian Institute of Technology Bombay India Keywords cancer chemotherapy microtubules mitosis sanguinarine tubulin Correspondence D. Panda School of Biosciences and Bioengineering Indian Institute of Technology Bombay Powai Mumbai 400 076 India Fax 91 22 25723480 Tel 91 22 25767838 E-mail panda@ Received 11 January 2006 revised 2 March 2006 accepted 13 March 2006 doi 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 keratino-cytes. 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 pM. 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 2 pM 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 40 pM it altered polymer morphology. Further it induced aggregation of tubulin in the presence of .