PMID- 28667329
OWN - NLM
STAT- MEDLINE
DCOM- 20190110
LR  - 20190110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jun 30
TI  - Imipramine blue sensitively and selectively targets FLT3-ITD positive acute 
      myeloid leukemia cells.
PG  - 4447
LID - 10.1038/s41598-017-04796-1 [doi]
LID - 4447
AB  - Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases 
      (RTKs) provides critical growth and survival signals in high risk acute myeloid 
      leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, 
      however, drug resistance limits clinical efficacy. Mutant receptor tyrosine 
      kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an 
      important role in the non-canonical activation of signal transducer and activator 
      of transcription 5 (STAT5). Here, we have tested a potent new drug called 
      imipramine blue (IB), which is a chimeric molecule with a dual mechanism of 
      action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through 
      liberation of endogenous phosphatase activity following NADPH oxidase (NOX) 
      inhibition. However, at 75-150 nM concentrations, IB was highly effective at 
      killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin 
      (TG), involving increased cytosolic calcium. IB also potently inhibited survival 
      of primary human FLT3/ITD(+) AML cells compared to FLT3/ITD(neg) cells and spared 
      normal umbilical cord blood cells. Therefore, IB functions through a mechanism 
      involving vulnerability to dysregulated calcium metabolism and the combination of 
      fusing a lipophilic amine to a NOX inhibiting dye shows promise for further 
      pre-clinical development for targeting high risk AML.
FAU - Metts, Jonathan
AU  - Metts J
AD  - Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, 
      USA.
AD  - Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 
      Atlanta, GA, USA.
FAU - Bradley, Heath L
AU  - Bradley HL
AD  - Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, 
      USA.
AD  - Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 
      Atlanta, GA, USA.
FAU - Wang, Zhengqi
AU  - Wang Z
AD  - Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, 
      USA.
AD  - Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 
      Atlanta, GA, USA.
FAU - Shah, Neil P
AU  - Shah NP
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      CA, USA.
FAU - Kapur, Reuben
AU  - Kapur R
AD  - Department of Pediatrics, Indiana University, Indianapolis, IA, USA.
FAU - Arbiser, Jack L
AU  - Arbiser JL
AD  - Department of Dermatology, Emory University, Atlanta, GA, USA.
AD  - Atlanta Veterans Administration Medical Center, Decatur, GA, 30033, USA.
FAU - Bunting, Kevin D
AU  - Bunting KD
AD  - Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, 
      USA. Kevin.bunting@emory.edu.
AD  - Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 
      Atlanta, GA, USA. Kevin.bunting@emory.edu.
LA  - eng
GR  - R01 AR047901/AR/NIAMS NIH HHS/United States
GR  - R01 CA173852/CA/NCI NIH HHS/United States
GR  - R01 DK059380/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170630
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (STAT5 Transcription Factor)
RN  - EC 2.7.10.1 (FLT3 protein, human)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
RN  - OGG85SX4E4 (Imipramine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
CIN - Fed Regist. 2017 Nov 27;82(226):56042-56043. PMID: 30378596
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Calcium/metabolism
MH  - Cell Line, Tumor
MH  - Cytosol/metabolism
MH  - *Gene Duplication
MH  - Humans
MH  - Imipramine/*pharmacology
MH  - Leukemia, Myeloid, Acute/*genetics/metabolism
MH  - Lysosomes/metabolism
MH  - Mitochondria/drug effects/genetics/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - STAT5 Transcription Factor/metabolism
MH  - *Tandem Repeat Sequences
MH  - fms-Like Tyrosine Kinase 3/*genetics/metabolism
PMC - PMC5493614
COIS- Jack L Arbiser is listed as inventor on a US Patent for imipramine blue. He is 
      co-founder of ABBY Therapeutics, which has licensed imipramine blue from Emory 
      University.
EDAT- 2017/07/02 06:00
MHDA- 2019/01/11 06:00
PMCR- 2017/06/30
CRDT- 2017/07/02 06:00
PHST- 2017/03/08 00:00 [received]
PHST- 2017/04/20 00:00 [accepted]
PHST- 2017/07/02 06:00 [entrez]
PHST- 2017/07/02 06:00 [pubmed]
PHST- 2019/01/11 06:00 [medline]
PHST- 2017/06/30 00:00 [pmc-release]
AID - 10.1038/s41598-017-04796-1 [pii]
AID - 4796 [pii]
AID - 10.1038/s41598-017-04796-1 [doi]
PST - epublish
SO  - Sci Rep. 2017 Jun 30;7(1):4447. doi: 10.1038/s41598-017-04796-1.