title: Effects of mTOR and calcineurin inhibitors combined therapy in Epstein-Barr virus positive and negative Burkitt lymphoma cells.
abstract: Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein-Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.
authors.affiliation: Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: Sylvia.wowro@charite.de.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Wowro
authors.affiliation: Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Katharina R L
authors.initials: KRL
authors.lastname: Schmitt
authors.affiliation: Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Giang
authors.initials: G
authors.lastname: Tong
authors.affiliation: Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Pediatric Cardiology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.affiliation: Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schubert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D019703:Calcineurin / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D000068338:Everolimus / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016559:Tacrolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D016559:Tacrolimus
keywords: Burkitt lymphoma; Cyclosporin A; Everolimus; PTLD; Pediatric transplant recipients; Tacrolimus