PMID- 20844237
OWN - NLM
STAT- MEDLINE
DCOM- 20110208
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 116
IP  - 25
DP  - 2010 Dec 16
TI  - 8-Aminoadenosine inhibits Akt/mTOR and Erk signaling in mantle cell lymphoma.
PG  - 5622-30
LID - 10.1182/blood-2010-05-285866 [doi]
AB  - 8-Aminoadenosine (8-NH(2)-Ado), a ribosyl nucleoside analog, in preclinical 
      models of multiple myeloma inhibits phosphorylation of proteins in multiple 
      growth and survival pathways, including Akt. Given that Akt controls the activity 
      of mammalian target of rapamycin (mTOR), we hypothesized that 8-NH(2)-Ado would 
      be active in mantle cell lymphoma (MCL), a hematological malignancy clinically 
      responsive to mTOR inhibitors. In the current study, the preclinical efficacy of 
      8-NH(2)-Ado and its resulting effects on Akt/mTOR and 
      extracellular-signal-regulated kinase signaling were evaluated using 4 MCL cell 
      lines, primary MCL cells, and normal lymphocytes from healthy donors. For all MCL 
      cell lines, 8-NH(2)-Ado inhibited growth and promoted cell death as shown by 
      reduction of thymidine incorporation, loss of mitochondrial membrane potential, 
      and poly (adenosine diphosphate-ribose) polymerase cleavage. The efficacy of 
      8-NH(2)-Ado was highly associated with intracellular accumulation of 
      8-NH(2)-adenosine triphosphate (ATP) and loss of endogenous ATP. Formation of 
      8-NH(2)-ATP was also associated with inhibition of transcription and translation 
      accompanied by loss of phosphorylated (p-)Akt, p-mTOR, p-Erk1/2, p-phosphoprotein 
      (p)38, p-S6, and p-4E-binding protein 1. While normal lymphocytes accumulated 
      8-NH(2)-ATP but maintained their viability with 8-NH(2)-Ado treatment, primary 
      lymphoma cells accumulated higher concentrations of 8-NH(2)-ATP, had increased 
      loss of ATP, and underwent apoptosis. We conclude that 8-NH(2)-Ado is efficacious 
      in preclinical models of MCL and inhibits signaling of Akt/mTOR and Erk pathways.
FAU - Dennison, Jennifer B
AU  - Dennison JB
AD  - Department of Experimental Therapeutics, The University of Texas M. D. Anderson 
      Cancer Center, Houston, TX, USA.
FAU - Shanmugam, Mala
AU  - Shanmugam M
FAU - Ayres, Mary L
AU  - Ayres ML
FAU - Qian, Jun
AU  - Qian J
FAU - Krett, Nancy L
AU  - Krett NL
FAU - Medeiros, L Jeffrey
AU  - Medeiros LJ
FAU - Neelapu, Sattva S
AU  - Neelapu SS
FAU - Rosen, Steven T
AU  - Rosen ST
FAU - Gandhi, Varsha
AU  - Gandhi V
LA  - eng
GR  - P50 CA136411/CA/NCI NIH HHS/United States
GR  - R01 CA085915/CA/NCI NIH HHS/United States
GR  - R01CA 85915/CA/NCI NIH HHS/United States
GR  - CA136411/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100915
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (RNA, Messenger)
RN  - 3868-33-5 (8-aminoadenosine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/*analogs & derivatives/pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors/metabolism
MH  - Flow Cytometry
MH  - Humans
MH  - Lymphoma, Mantle-Cell/drug therapy/metabolism/*pathology
MH  - Phosphorylation/drug effects
MH  - Protein Biosynthesis/drug effects
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Cells, Cultured
PMC - PMC3031409
EDAT- 2010/09/17 06:00
MHDA- 2011/02/09 06:00
PMCR- 2011/12/16
CRDT- 2010/09/17 06:00
PHST- 2010/09/17 06:00 [entrez]
PHST- 2010/09/17 06:00 [pubmed]
PHST- 2011/02/09 06:00 [medline]
PHST- 2011/12/16 00:00 [pmc-release]
AID - S0006-4971(20)60358-5 [pii]
AID - 2010/285866 [pii]
AID - 10.1182/blood-2010-05-285866 [doi]
PST - ppublish
SO  - Blood. 2010 Dec 16;116(25):5622-30. doi: 10.1182/blood-2010-05-285866. Epub 2010 
      Sep 15.