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Inhibitor Imatinib (inhibitor + imatinib)
Selected AbstractsEmerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: Bidirectional translational scienceJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Bruce J. Dezube Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research,not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed. J. Cell. Physiol. 209: 659,662, 2006. © 2006 Wiley-Liss, Inc. [source] FAK silencing inhibits leukemogenesis in BCR/ABL-transformed hematopoietic cells,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2009Yi Le Focal adhesion kinase (FAK) is constitutively activated and tyrosine phosphorylated in BCR/ABL-transformed hematopoietic cells, but the role it plays during leukemogenesis remains unclear. Here, we examined the effects of RNA interference-mediated FAK silencing on leukemogenesis induced by a BCR/ABL-transformed cell line. Transduction of BCR/ABL-BaF3 cells with FAK shRNA inhibited FAK expression and reduced STAT5 phosphorylation, but induced caspase-3 activation. In vitro studies showed that treatment with FAK shRNA resulted in impaired cell proliferation and colony formation, while increasing cell apoptosis. Mice that received transplants of BCR/ABL-BaF3 cells with FAK shRNA displayed significantly prolonged survival time and diminished leukemia progression. In addition, FAK silencing enhanced in vitro and in vivo efficacy of ABL tyrosine kinase inhibitor imatinib in BCR/ABL-BaF3 cells. Our results suggest that FAK is critical for leukemogenesis and might be a potential target for leukemia therapy. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Triptolide abrogates oncogene FIP1L1-PDGFR, addiction and induces apoptosis in hypereosinophilic syndromeCANCER SCIENCE, Issue 11 2009Yanli Jin The pathogenesis of hypereosinophilic syndrome (HES) in some patients is highly dependent on FIP1-Like-1 (FIP1L1),platelet-derived growth factor receptor alpha (PDGFR,), which can generate sustained activation signaling to maintain a cell malignant phenotype. HES usually shows good response to the tyrosine kinase inhibitor imatinib, but mutations in FIP1L1-PDGFR, (e.g. T674I) can confer acquired resistance to imatinib. An alternative therapeutic strategy other than with tyrosine kinase inhibitors is needed to overcome acquired drug resistance. We hypothesized that switching off the crucial chimeric oncoprotein FIP1L1-PDGFR, on which HES cells depend, should have deleterious effects on the cancer cells. We used low concentrations of triptolide, a transcription inhibitor, to shut down the expression of FIP1L1-PDGFR,. EOL-1 cells and BaF3 cells expressing wild-type or T674I FIP1L1-PDGFR, were treated with triptolide, and signaling pathways, cell cycling, and apoptosis were analyzed by RT-PCR, immunoblotting, and flow cytometry, respectively. The results revealed that at nanomolar concentrations triptolide decreased the levels of mRNA and protein of FIP1L1-PDGFR, and the growth of the neoplastic cells, regardless of the mutational status of PDGFR,. Triptolide also downregulated the signaling molecules Stat3, Akt, and Erk1/2, which are downstream from PDGFR,, and induced G1 cell-cycle arrest. Triptolide time- and dose-dependently induced apoptosis by decreasing the anti-apoptotic proteins Mcl-1 and Bcl-XL,triggering the intrinsic apoptotic pathway. In conclusion, triptolide has potent activity against malignant cells in HES bearing FIP1L1-PDGFR,, regardless of its mutational status that confer acquired resistance to imatinib. Our results suggest that triptolide may be a promising agent in the treatment of HES. (Cancer Sci 2009; 00: 000,000) [source] Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligandCANCER SCIENCE, Issue 12 2007Satoru Kikuchi FKHRL1 (also called FOXO3a) is a member of the Forkhead Box, class O (FOXO) subfamily of forkhead transcription factors and functions downstream of Bcr,Abl tyrosine kinase as a phosphorylated inactive form in chronic myelogenous leukemia (CML). The Bcr,Abl tyrosine kinase inhibitor imatinib induces cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated inactive form to the dephosphorylated active form in CML-derived cell lines. In the present study, we examined whether active FKHRL1 can overcome resistance to imatinib. To this end, we generated a 4-hydroxytamoxifen-inducible active FKHRL1 (FKHRL1-TM; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated),estrogen receptor fusion protein expression system in CML-derived imatinib-resistant cell lines. 4-Hydroxytamoxifen inhibited cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, active FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines. In addition, imatinib-resistant cells underwent apoptosis after transfection with full-length TRAIL cDNA. Collectively, our results suggest that active FKHRL1 can overcome imatinib resistance in CML cells, in part via TRAIL production. (Cancer Sci 2007; 98: 1949,1958) [source] | ||||||||||