PMID- 27494886
OWN - NLM
STAT- MEDLINE
DCOM- 20180205
LR  - 20211204
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 34
DP  - 2016 Aug 23
TI  - Healthy CD4+ T lymphocytes are not affected by targeted therapies against the 
      PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia.
PG  - 55690-55703
LID - 10.18632/oncotarget.10984 [doi]
AB  - An attractive molecular target for novel anti-cancer therapies is the 
      phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) 
      pathway which is commonly deregulated in many types of cancer. Nevertheless, the 
      effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune 
      responses, have been seldom explored. In this study we investigated the effects 
      on human CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, 
      MK-2206, and ZSTK474. We also assessed their efficacy against two acute leukemia 
      T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor 
      effects on cell cycle and apoptosis were analyzed by flow cytometry, while 
      cytotoxicity was assessed by MTT assays. In addition, the activation status of 
      the pathway as well as induction of autophagy were analyzed by Western blotting. 
      Quiescent healthy T lymphocytes were unaffected by the drugs whereas 
      mitogen-stimulated lymphocytes as well as leukemic cell lines displayed a cell 
      cycle block, caspase-dependent apoptosis, and dephosphorylation of key components 
      of the signaling pathway. Autophagy was also induced in proliferating lymphocytes 
      and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 
      3-methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating 
      that autophagy is a protective mechanism. Therefore, our findings suggest that 
      PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result 
      to be taken into account when selecting drugs for targeted cancer therapy in 
      order to minimize detrimental effects on immune function.
FAU - Alameen, Ayman A M
AU  - Alameen AA
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
AD  - Department of Chemical Pathology, Faculty of Medical Laboratory Sciences, 
      University of Khartoum, Khartoum, Sudan.
FAU - Simioni, Carolina
AU  - Simioni C
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
FAU - Martelli, Alberto M
AU  - Martelli AM
AD  - Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 
      Italy.
FAU - Zauli, Giorgio
AU  - Zauli G
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
FAU - Ultimo, Simona
AU  - Ultimo S
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
FAU - McCubrey, James A
AU  - McCubrey JA
AD  - Department of Microbiology & Immunology, Brody School of Medicine, East Carolina 
      University, Greenville, NC, USA.
FAU - Gonelli, Arianna
AU  - Gonelli A
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
FAU - Marisi, Giorgia
AU  - Marisi G
AD  - Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei 
      Tumori (IRST) IRCCS, Meldola, Italy.
FAU - Ulivi, Paola
AU  - Ulivi P
AD  - Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei 
      Tumori (IRST) IRCCS, Meldola, Italy.
FAU - Capitani, Silvano
AU  - Capitani S
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
AD  - LTTA Center, University of Ferrara, Ferrara, Italy.
FAU - Neri, Luca M
AU  - Neri LM
AD  - Department of Morphology, Surgery and Experimental Medicine, University of 
      Ferrara, Ferrara, Italy.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 
      (8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one)
RN  - 0 
      (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Imidazoles)
RN  - 0 (Naphthyridines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Autophagy/drug effects
MH  - CD4-Positive T-Lymphocytes/*drug effects/immunology
MH  - Cell Line, Tumor
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Lymphocyte Activation
MH  - Molecular Targeted Therapy
MH  - Naphthyridines/pharmacology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/immunology/pathology
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors
MH  - Quinolines/pharmacology
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC5342446
OTO - NOTNLM
OT  - PI3K/Akt/mTOR signaling
OT  - T lymphocytes
OT  - T-acute lymphoblastic leukemia
OT  - autophagy
OT  - targeted therapies
COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest.
EDAT- 2016/08/06 06:00
MHDA- 2018/02/06 06:00
PMCR- 2016/08/23
CRDT- 2016/08/06 06:00
PHST- 2016/05/05 00:00 [received]
PHST- 2016/07/11 00:00 [accepted]
PHST- 2016/08/06 06:00 [pubmed]
PHST- 2018/02/06 06:00 [medline]
PHST- 2016/08/06 06:00 [entrez]
PHST- 2016/08/23 00:00 [pmc-release]
AID - 10984 [pii]
AID - 10.18632/oncotarget.10984 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Aug 23;7(34):55690-55703. doi: 10.18632/oncotarget.10984.