Regulation of Vinca alkaloid-induced apoptosis by NF-KB/IKB pathway in human tumor cells

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 IKBA, which in turn results in nuclear factor-KB (NF-KB) activation. Transfection of antisense IKBA in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IKB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IKBA, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-KB activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-KB/IKB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells. [Mol Cancer Ther. 2004;3(3):271–277]