PMID- 21064094
OWN - NLM
STAT- MEDLINE
DCOM- 20110930
LR  - 20211203
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 129
IP  - 4
DP  - 2011 Aug 15
TI  - Inhibition of mammalian target of rapamycin signaling by everolimus induces 
      senescence in adult T-cell leukemia/lymphoma and apoptosis in peripheral T-cell 
      lymphomas.
PG  - 993-1004
LID - 10.1002/ijc.25742 [doi]
AB  - HTLV-I-associated adult T-cell leukemia/lymphoma (ATL) and human T-cell 
      lymphotropic virus type I (HTLV-I)-negative peripheral T-cell lymphomas carry 
      poor prognosis mainly because of acquired resistance to chemotherapy. We have 
      shown that this disease is responsive to the combination of zidovudine and 
      interferon-alpha. However, long-term maintenance therapy with this combination is 
      associated with side effects affecting patient quality of life and hence more 
      tolerated alternatives are needed. In this submission, we explored the effect of 
      the mammalian target of rapamycin (mTOR) complex-1 (mTORC1) inhibitor everolimus 
      (RAD001) on ATL and HTLV-negative malignant T-cell lines. We demonstrate that, at 
      clinically achievable concentrations, long-term treatment with everolimus 
      resulted in a dramatic inhibitory effect on the growth of HTLV-I-positive and 
      -negative malignant T-cells, while normal resting or activated T-lymphocytes were 
      resistant. Everolimus specifically induced oncoprotein Tax degradation and 
      senescence in ATL cells and cell cycle arrest and apoptosis in HTLV-I-negative 
      malignant T-cells. Everolimus-mediated apoptosis was also associated with an 
      upregulation of p53 upregulated modulator of apoptosis (PUMA-alpha) proteins, an 
      increase in Bax proteins and downregulation of Bcl-x(L) proteins in all tested 
      HTLV-I-positive and -negative malignant cell lines. These results support a 
      therapeutic role for everolimus, particularly as long-term maintenance therapy in 
      patients with ATL and other HTLV-I-negative peripheral T-cell lymphomas.
CI  - Copyright (c) 2010 UICC.
FAU - Darwiche, Nadine
AU  - Darwiche N
AD  - Department of Biology, American University of Beirut, Beirut, Lebanon. 
      nd03@aub.edu.lb
FAU - Sinjab, Ansam
AU  - Sinjab A
FAU - Abou-Lteif, Ghada
AU  - Abou-Lteif G
FAU - Chedid, Mirella Bou
AU  - Chedid MB
FAU - Hermine, Olivier
AU  - Hermine O
FAU - Dbaibo, Ghassan
AU  - Dbaibo G
FAU - Bazarbachi, Ali
AU  - Bazarbachi A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101209
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BAX protein, human)
RN  - 0 (BBC3 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Cells, Cultured
MH  - *Cellular Senescence
MH  - Everolimus
MH  - G1 Phase/drug effects
MH  - Human T-lymphotropic virus 1/metabolism
MH  - Humans
MH  - Leukemia-Lymphoma, Adult T-Cell/*drug therapy/metabolism/pathology
MH  - Lymphoma, T-Cell, Peripheral/*drug therapy/metabolism/pathology
MH  - Proto-Oncogene Proteins/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - T-Lymphocytes/drug effects/metabolism
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Tumor Suppressor Protein p53/metabolism
MH  - bcl-2-Associated X Protein/metabolism
EDAT- 2010/11/11 06:00
MHDA- 2011/10/01 06:00
CRDT- 2010/11/11 06:00
PHST- 2010/05/12 00:00 [received]
PHST- 2010/09/27 00:00 [accepted]
PHST- 2010/11/11 06:00 [entrez]
PHST- 2010/11/11 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
AID - 10.1002/ijc.25742 [doi]
PST - ppublish
SO  - Int J Cancer. 2011 Aug 15;129(4):993-1004. doi: 10.1002/ijc.25742. Epub 2010 Dec 
      9.