Abstract
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.
Footnotes
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This study was partially supported by the MJF Foundation (to H.B.B.) and The Karyn Research Fund (to A.L.).
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DOI: 10.1124/jpet.102.036723
- Abbreviations:
- ALL
- acute lymphoblastic leukemia
- B-NHL
- non-Hodgkin B lymphoma
- PTK
- protein tyrosine kinase
- CML
- chronic myelogenous leukemia
- FCS
- fetal calf serum
- Med
- RPMI 1640 medium without phenol red, with 10% fetal calf serum and antibiotics
- DMSO
- dimethyl sulfoxide
- XXT
- 2,3-bis[2-methoxy-4-nitro-5-sulfo-phenyl]-2H-tetrazolium-5-carboxyanilide
- PMS
- phenazine methosulfate
- PBS
- phosphate-buffered saline
- FACS
- fluorescence-activated cell sorting
- DAPI
- 4,6-diamidino-2-phenylindole
- Received April 2, 2002.
- Accepted June 3, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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