Suppression of proliferation and phosphorylation of Jak3 and STAT5 in malignant T-cell lymphoma cells by derivatives of octylamino-undecyl-dimethylxanthine.
IL-2R signal transduction involves tyrosine phosphorylation of several proteins including Jak3 and STAT5. In the present study we examined the effect of two octylamino-undecyl-dimethylxanthine (OUDMX) derivatives, designated CT2576 and CT5589, on proliferation and protein tyrosine phosphorylation in human malignant T-cell lymphoma lines. These T-cell lines (PB-1, 2A, and 2B), obtained from a progressive T-cell lymphoma involving skin, are IL-2 independent but have constitutively activated IL-2R-associated signal transduction pathway common to IL-2 and several other cytokines: IL-4, IL-7, IL-9, and IL-15. CT2576, characterized previously on the functional level as an inhibitor of IL-2 signaling and, on the biochemical level, as an inhibitor of phosphatidic acid biosynthesis, suppressed completely growth of the malignant T cell lymphoma lines. CT5589 which is a novel analog of the CT2576, displayed a similar, although weaker, effect. Furthermore, both CT compounds inhibited constitutive tyrosine phosphorylation of two proteins: Jak3 and STAT5 which are key downstream elements in the signal transduction pathway activated by IL-2 and the other cytokines. The CT compounds inhibited also Jak3 phosphorylation induced by IL-2 in the IL-2 dependent SZ-4 cells. Inhibition of phosphorylation by CT2576 and CT5589 was only partially selective since phosphorylation of several other proteins was also affected. Phosphorylation of many others was, however, unaffected. These findings demonstrate that the OUDMX derivatives suppress proliferation of malignant T lymphocytes. Furthermore, they suggest that this suppression may be mediated by inhibition of the IL-2R-associated Jak/STAT signaling pathway. A potential role for OUDMX derivatives in therapy of human T-cell lymphoma should be further explored.
Wasik
M A
MA
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Nowak
I
I
Zhang
Q
Q
Shaw
L M
LM
D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D053616:Janus Kinase 3; D016399:Lymphoma, T-Cell / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008894:Milk Proteins; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology*
D000970:Antineoplastic Agents; C093734:CT 2576; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014970:Xanthines; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3