Vol. 303, Issue 1, 163-171, October 2002

Tyrosine Kinase Inhibitors Suppress the Growth of Non-Hodgkin B Lymphomas

Hannah Ben-Bassat, Zipora Hartzstark, Rubina Levitzki, Benjamin Y. Klein, Zipora Shlomai, Aviv Gazit and Alexander Levitzki

Laboratory of Experimental Surgery, Hadassah University Hospital (H.B.B., Z.H., R.L., B.J.K., Z.S.); Unit of Cellular Signaling, Department of Biological Chemistry, Silberman Institute of Life Sciences (A.L.); and Department of Organic Chemistry, Institute of Chemistry (A.G.), The Hebrew University, Jerusalem, Israel

Non-Hodgkin lymphomas usually become resistant to chemotherapy and relapse due to the their intense antiapoptotic robustness. Furthermore, the slow growth of these malignancies limits the effectiveness of drugs aimed mainly at the proliferative pathways. Because protein tyrosine kinases (PTKs) play a key role in both proliferative and antiapoptotic pathways we screened our library of PTK inhibitors for agents that induce growth arrest and apoptosis in non-Hodgkin B cell lymphoma cell lines. Herein, we describe the identification of a family of PTK inhibitors whose most potent member is AGL 2592. This agent induces growth arrest and massive apoptosis in a number of non-Hodgkin lymphoma cell lines. We also show that the lymphoma cell lines are much more sensitive to this class of agents compared with other malignant carcinoma cells. AGL 2592 induces a dose-dependent and time-dependent inhibition of tyrosine phosphorylation of numerous proteins, including Stat3, and an increase of Bcl-2 phosphorylation, both biochemical hallmarks of growth inhibition and apoptosis.