Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α |
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| Institution: | 1. Immunobiology Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India;2. Department of Pathology, Burdwan Medical College, Burdwan, West Bengal, India;3. Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India;4. Department of Zoology, The University of Burdwan, Burdwan, West Bengal, India;5. Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India;1. Department of Neurosurgery, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Saar, Germany;2. Department of Neurosurgery, University of Alabama at Birmingham, AL, United States;3. Department of Neurosciences, Inova Health System, Falls Church, VA, United States;4. Department of Molecular Neuroscience, George Mason University, Fairfax, VA, United States;5. Seattle Science Foundation, Seattle, WA, United States;6. Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;7. Department of Anesthesiology, University of Alabama at Birmingham, AL, United States;8. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States;9. Department of Neurosurgery, Geisinger Health System, Danville, PA, United States;1. Service d''Histologie-Embryologie-Cytogénétique, Hôpitaux Universitaires Paris-Sud, Site Antoine Béclère, APHP, Clamart, France;2. Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital Bicêtre, APHP, Le Kremlin-Bicêtre, France;3. Génétique Moléculaire, Hôpitaux Universitaires Paris-Sud, Site Antoine Béclère, APHP, Clamart, France;4. INSERM U935, Villejuif, France;5. Service de Biochimie-Génétique, Plateforme de Génétique Constitutionnelle, Hôpital H. Mondor, APHP, Créteil, France;6. INSERM U955, Plateforme de Génétique Constitutionnelle, Hôpital H. Mondor, Créteil, France;7. Unité de F?topathologie, Hôpitaux Universitaires Paris-Sud, Site Antoine Béclère, APHP, Clamart, France;8. Service de Gynécologie Obstétrique, Hôpitaux Universitaires Paris-Sud, Site Antoine Béclère, APHP, Clamart, France;1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;2. Department of Hematology, XiangYa Hospital, Central South University, Changsha, China;3. Department of Medicine, University of British Columbia, Vancouver, Canada;1. Wuxi Mental Health Center, Nanjing Medical University, 156 Qianrong Road, Wuxi 214151, Jiangsu Province, China;2. Divsion of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Building 35, Room 3A 1000, 35 Convent Drive, Bethesda, MD 20892, USA |
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| Abstract: | Although disputed by some, increasing evidence suggests that TNF-α synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-α is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-α. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-α upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF-α expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma. |
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| Keywords: | TNF-α Dendritic cells IL-15 Doxorubicin Drug resistance STAT3 |
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