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¹ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC and ² Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

Requests for Reprints: Weimin Fan, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425. Phone: (843) 792-5108; Fax: (843) 792-0368. E-mail: fanw{at}musc.edu

Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere with the dynamics of microtubules and have shown significant cell killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In this study, we found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis without affecting G₂-M arrest in human breast cancer BCap37 cells and human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis may occur via a pathway independent of cell cycle arrest. Further analyses indicated that Vinca alkaloids cause significant degradation of IB, which in turn results in nuclear factor-B (NF-B) activation. Transfection of antisense IB in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IB, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-B activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-B/IB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells.

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Received 8/12/03; revised 11/19/03; accepted 12/ 9/03.