PMID- 26613512
OWN - NLM
STAT- MEDLINE
DCOM- 20160930
LR  - 20211203
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 30
DP  - 2016 Jan
TI  - Effects of mTOR and calcineurin inhibitors combined therapy in Epstein-Barr virus 
      positive and negative Burkitt lymphoma cells.
PG  - 9-17
LID - S1567-5769(15)30188-0 [pii]
LID - 10.1016/j.intimp.2015.11.020 [doi]
AB  - 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.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Wowro, Sylvia J
AU  - Wowro SJ
AD  - Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches 
      Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic 
      address: Sylvia.wowro@charite.de.
FAU - Schmitt, Katharina R L
AU  - Schmitt KRL
AD  - Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches 
      Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
FAU - Tong, Giang
AU  - Tong G
AD  - Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches 
      Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
FAU - Berger, Felix
AU  - Berger F
AD  - Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches 
      Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of 
      Pediatric Cardiology, Charite-Universitatsmedizin Berlin, Augustenburger Platz 1, 
      13353 Berlin, Germany.
FAU - Schubert, Stephan
AU  - Schubert S
AD  - Department of Congenital Heart Defects/Pediatric Cardiology, Deutsches 
      Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151121
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunosuppressive Agents)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (Calcineurin)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Burkitt Lymphoma/complications/*drug therapy/immunology
MH  - Calcineurin/metabolism
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cyclosporine/*pharmacology
MH  - Drug Therapy, Combination
MH  - Epstein-Barr Virus Infections/complications/*drug therapy/immunology
MH  - Everolimus/*pharmacology
MH  - Herpesvirus 4, Human/*immunology
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Mitochondria/*drug effects/physiology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Tacrolimus/*pharmacology
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Burkitt lymphoma
OT  - Cyclosporin A
OT  - Everolimus
OT  - PTLD
OT  - Pediatric transplant recipients
OT  - Tacrolimus
EDAT- 2015/11/28 06:00
MHDA- 2016/10/01 06:00
CRDT- 2015/11/28 06:00
PHST- 2015/07/09 00:00 [received]
PHST- 2015/10/21 00:00 [revised]
PHST- 2015/11/16 00:00 [accepted]
PHST- 2015/11/28 06:00 [entrez]
PHST- 2015/11/28 06:00 [pubmed]
PHST- 2016/10/01 06:00 [medline]
AID - S1567-5769(15)30188-0 [pii]
AID - 10.1016/j.intimp.2015.11.020 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2016 Jan;30:9-17. doi: 10.1016/j.intimp.2015.11.020. Epub 
      2015 Nov 21.