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The Tyrphostin AG17 Induces Apoptosis and Inhibition of cdk2 Activity in a Lymphoma Cell Line That Overexpresses bcl-2¹

Institute of Hematology, University of Catania, 95124 Catania, Italy [G. A. P.] and Department of Hematology, Hadassah University Hospital, Ein-Kerem, P.O. Box 12000, [N. Y., Z. S., D. B-Y.], Department of Biological Chemistry, the Institute of Life Sciences [A. G., N. K-D., A. L.], and Lautenberg Center for Immunology [M. B.], The Hebrew University, Jerusalem 91120, Israel

Tyrphostins are low molecular weight compounds that specifically inhibit protein tyrosine kinases. We studied the effects of tyrphostins on OCI-Ly8, a cell line derived from a patient with immunoblastic lymphoma that carries the t(14;18) translocation and overexpresses the B-cell lymphoma/leukemia-2 gene (bcl-2). To test the possibility that tyrphostins induce apoptosis in these cells, overcoming the protection rendered by bcl-2, we screened 16 tyrphostins representing different families at a concentration of 0.5–50 µM. We found that AG17 was the most potent in this regard. Cell cycle analysis demonstrated that AG17 induces arrest at the G₁ phase followed by apoptosis with general reduction of the intracellular level of tyrosine-phosphorylated proteins. To further elucidate the mechanism of action of AG17, we investigated its effect on some of the key proteins that regulate the cell cycle. Bcl-2 and cdk2 protein levels were not altered with AG17, whereas cdk2 kinase activity, as well as p21 and p16 protein levels, were reduced markedly. These results suggest that the target of AG17 is inactivation of cdk2. Because lymphoma cells with the t(14;18) translocation and bcl-2 overexpression are resistant to chemotherapy, novel drugs selectively able to induce apoptosis in these cells could offer a new approach to the treatment of lymphoma patients.

¹ G. A. Palumbo was supported by the Fondazione Catanese Per Lo Studio E La Cura Delle Malattie Neoplastiche Del Sangue.

² To whom requests for reprints should be addressed, at Department of Hematology, Hadassah University Hospital, Jerusalem 91120, Israel. Phone: 972-2-6776744; Fax: 972-2-6423067.

Received 11/21/96. Accepted 4/ 9/97.

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