PMID- 23509154
OWN - NLM
STAT- MEDLINE
DCOM- 20130704
LR  - 20211021
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 121
IP  - 18
DP  - 2013 May 2
TI  - Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on 
      acute myeloid leukemia precursors.
PG  - 3675-81
LID - 10.1182/blood-2013-01-477216 [doi]
AB  - Mnk kinases regulate the phosphorylation and activation of the eukaryotic 
      initiation factor 4E (eIF4E), a protein that plays key roles in the initiation of 
      messenger RNA translation and whose activity is critical for various cellular 
      functions. eIF4E is deregulated in acute myeloid leukemia (AML), and its aberrant 
      activity contributes to leukemogenesis. We determined whether cercosporamide, an 
      antifungal agent that was recently shown to act as a unique Mnk inhibitor, 
      exhibits antileukemic properties. Treatment of AML cells with cercosporamide 
      resulted in a dose-dependent suppression of eIF4E phosphorylation. Such 
      suppression of Mnk kinase activity and eIF4E phosphorylation by cercosporamide 
      resulted in dose-dependent suppressive effects on primitive leukemic progenitors 
      (CFU-L) from AML patients and enhanced the antileukemic properties of cytarabine 
      (Ara-C) or mammalian target of rapamycin (mTOR) complex 1 inhibition. Similarly, 
      the combination of cercosporamide with cytarabine resulted in enhanced 
      antileukemic responses in a xenograft mouse model in vivo. Altogether, this work 
      demonstrates that the unique Mnk inhibitor cercosporamide suppresses 
      phosphorylation of eIF4E and exhibits antileukemic effects, in support of future 
      clinical-translational efforts involving combinations of Mnk inhibitors with 
      cytarabine and/or mTOR inhibitors for the treatment of AML.
FAU - Altman, Jessica K
AU  - Altman JK
AD  - Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, 
      Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
FAU - Szilard, Amy
AU  - Szilard A
FAU - Konicek, Bruce W
AU  - Konicek BW
FAU - Iversen, Philip W
AU  - Iversen PW
FAU - Kroczynska, Barbara
AU  - Kroczynska B
FAU - Glaser, Heather
AU  - Glaser H
FAU - Sassano, Antonella
AU  - Sassano A
FAU - Vakana, Eliza
AU  - Vakana E
FAU - Graff, Jeremy R
AU  - Graff JR
FAU - Platanias, Leonidas C
AU  - Platanias LC
LA  - eng
GR  - R01 CA121192/CA/NCI NIH HHS/United States
GR  - R01 CA077816/CA/NCI NIH HHS/United States
GR  - P30 CA060553/CA/NCI NIH HHS/United States
GR  - CA155566/CA/NCI NIH HHS/United States
GR  - CA121192/CA/NCI NIH HHS/United States
GR  - R01 CA155566/CA/NCI NIH HHS/United States
GR  - CA77816/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130318
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzofurans)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 131436-22-1 (cercosporamide)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 7.2.2.8 (ATP7A protein, human)
RN  - EC 7.2.2.8 (Copper-Transporting ATPases)
SB  - IM
MH  - Adenosine Triphosphatases/*antagonists & inhibitors
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Benzofurans/*therapeutic use
MH  - Cation Transport Proteins/*antagonists & inhibitors
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Copper-Transporting ATPases
MH  - Down-Regulation/drug effects
MH  - Humans
MH  - K562 Cells
MH  - Leukemia, Myeloid, Acute/*drug therapy
MH  - Mice
MH  - Neoplastic Stem Cells/drug effects
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - U937 Cells
MH  - Xenograft Model Antitumor Assays
PMC - PMC3643766
EDAT- 2013/03/20 06:00
MHDA- 2013/07/05 06:00
PMCR- 2014/05/02
CRDT- 2013/03/20 06:00
PHST- 2013/03/20 06:00 [entrez]
PHST- 2013/03/20 06:00 [pubmed]
PHST- 2013/07/05 06:00 [medline]
PHST- 2014/05/02 00:00 [pmc-release]
AID - S0006-4971(20)58716-8 [pii]
AID - 2013/477216 [pii]
AID - 10.1182/blood-2013-01-477216 [doi]
PST - ppublish
SO  - Blood. 2013 May 2;121(18):3675-81. doi: 10.1182/blood-2013-01-477216. Epub 2013 
      Mar 18.