PMID- 25758096
OWN - NLM
STAT- MEDLINE
DCOM- 20160224
LR  - 20211203
IS  - 1865-3774 (Electronic)
IS  - 0925-5710 (Linking)
VI  - 102
IP  - 1
DP  - 2015 Jul
TI  - The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute 
      myeloid leukemia cell lines lacking typical t(15;17) translocation.
PG  - 12-24
LID - 10.1007/s12185-015-1776-2 [doi]
AB  - Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients 
      with acute promyelocytic leukemia (APL), but is much less efficacious in acute 
      myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have 
      indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors 
      may increase the sensitivity of malignant cells to ATO. The aim of the present 
      study was to test for possible synergistic effects of ATO and rapamycin at 
      therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell 
      lines, the inhibitory effects of low concentrations of ATO and rapamycin were 
      synergistic and more pronounced in U937 cells. The combination of drugs increased 
      apoptosis in HL-60 cells and increased the percentage of cells in G(0)/G(1) phase 
      in both cell lines. In U937 cells, rapamycin alone increased the activity of 
      mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) 
      and the addition of ATO decreased the level of phosphorylated ERK, Ser473 
      phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high 
      sensitivity to growth-inhibitory effects of rapamycin alone or in combination 
      with ATO. The results of the present study reveal the mechanism of the 
      synergistic effects of two drugs at therapeutically achievable doses in non-APL 
      AML cells.
FAU - Dembitz, Vilma
AU  - Dembitz V
AD  - Department of Physiology and Croatian Institute for Brain Research, School of 
      Medicine, University of Zagreb, Salata 3, POB 978, 10 000, Zagreb, Croatia.
FAU - Lalic, Hrvoje
AU  - Lalic H
FAU - Ostojic, Alen
AU  - Ostojic A
FAU - Vrhovac, Radovan
AU  - Vrhovac R
FAU - Banfic, Hrvoje
AU  - Banfic H
FAU - Visnjic, Dora
AU  - Visnjic D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150311
PL  - Japan
TA  - Int J Hematol
JT  - International journal of hematology
JID - 9111627
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Arsenicals)
RN  - 0 (Oxides)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - S7V92P67HO (Arsenic Trioxide)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Aged
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Arsenic Trioxide
MH  - Arsenicals/*pharmacology
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Chromosomes, Human, Pair 15
MH  - Chromosomes, Human, Pair 17
MH  - Drug Synergism
MH  - Female
MH  - HL-60 Cells
MH  - Humans
MH  - Leukemia, Myeloid, Acute/drug therapy/*genetics/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Oxides/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Translocation, Genetic
EDAT- 2015/03/12 06:00
MHDA- 2016/02/26 06:00
CRDT- 2015/03/12 06:00
PHST- 2014/10/02 00:00 [received]
PHST- 2015/03/02 00:00 [accepted]
PHST- 2015/02/27 00:00 [revised]
PHST- 2015/03/12 06:00 [entrez]
PHST- 2015/03/12 06:00 [pubmed]
PHST- 2016/02/26 06:00 [medline]
AID - 10.1007/s12185-015-1776-2 [doi]
PST - ppublish
SO  - Int J Hematol. 2015 Jul;102(1):12-24. doi: 10.1007/s12185-015-1776-2. Epub 2015 
      Mar 11.