The γ-secretase inhibitor GSI-I interacts synergistically with the proteasome inhibitor bortezomib to induce ALK+ anaplastic large cell lymphoma cell apoptosis |
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| Institution: | 1. Hématologie Biologique, CHU Estaing, 1 Place Lucie Aubrac, 63003 Clermont-Ferrand Cedex 1, France;2. Hématologie Clinique, CHU Estaing, 1 Place Lucie Aubrac, 63003 Clermont-Ferrand Cedex 1, France;3. Hématologie et Médecine Interne, CHU Brabois, Rue Morvan, 54500 Vandoeuvre-lès-Nancy, France;4. Laboratoire Microorganismes, Génome et Environnement (LMGE) – UMR CNRS 6023, Université Blaise Pascal, UFR Sciences et Technologies, 24, avenue des Landais, BP 80026, 63171 Aubière Cedex, France;1. Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan;2. Japan Science Technology Agency, CREST, K׳s Gobancho, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan;1. Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL;;2. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL;;3. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;;4. Department of Laboratory Medicine, Section of Hematology and Transfusion Medicine, Lund University, Lund, Sweden;;5. Stanley Center for Psychiatric Research, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA;;6. Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA;;7. Department of Genetics, Harvard Medical School, Boston, MA;;8. Cote d''Azur University, Centre Hospitalier Universitaire of Nice, Nice, France;;9. Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford and Oxford Biomedical Research Centre Haematology Theme, Oxford, United Kingdom;;10. Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH;;11. Institut de Recerca Contra la Leucèmia Josep Carreras, Institut Catala d''Oncologia–Hospital GermansTrias i Pujol, Universitat Autonòma de Barcelona, Badalona, Barcelona, Spain;12. Laboratori de Citologia Hematòlogica, Servei de Patologia, Hospital del Mar, Barcelona, Spain;;13. Department of Haematological Medicine, Kings College London, London, United Kingdom;;14. Senior Hematology Department, Hopital Saint Louis, Paris, France;;15. Departments of Medicine and Medical Oncology, Harvard Medical School and Brigham and Women''s Hospital, Boston, MA;16. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL;2. Department of Biostatistics, University of Texas Southwestern Medical Center, Dallas, TX;3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX;4. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX;5. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX;11. VA North Texas Health Care System, Dallas, TX;1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. Department of Hematology, Capital Medical University Beijing Friendship Hospital, Beijing, China;3. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;1. Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, NY 10016, USA;2. NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA;3. Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA |
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| Abstract: | Single agent treatment of the γ-secretase inhibitor (GSI-I) or proteasome inhibitor in anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ ALCL) shows limited response and considerable toxicity. Here, we examined the effects of the combination of low dose GSI-I and the proteasome inhibitor bortezomib (BTZ) in ALK+ ALCL cells in vivo and in vitro. We found that ALK+ ALCL cells treated with the BTZ and GSI-I combination treatment showed elevated apoptosis, consistent with increased caspase activation, compared with BTZ or GSI-I alone. The combination treatment also inhibited AKT and extracellular signal-related kinase pathways, as well as stress-related cascades, including the c-jun N-terminal kinase and stress-activated kinases. Moreover, combined treatment in a murine xenograft model resulted in increased apoptosis in tumor tissues and reduced tumor growth. Our results reveal the synergistic anti-tumor effects of low dose inhibitors against γ-secretase and the proteasome and suggest the potential application of the tolerable BTZ/GSI-I combined agents in treating ALK+ ALCL in future clinical treatment. |
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