Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells

Abstract 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. Muta...

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Autores principales:	Jonathan Metts, Heath L. Bradley, Zhengqi Wang, Neil P. Shah, Reuben Kapur, Jack L. Arbiser, Kevin D. Bunting
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/194b5d0b84eb4fd8aa2867b88dfc9dc5
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spelling	oai:doaj.org-article:194b5d0b84eb4fd8aa2867b88dfc9dc52021-12-02T11:52:15ZImipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells10.1038/s41598-017-04796-12045-2322https://doaj.org/article/194b5d0b84eb4fd8aa2867b88dfc9dc52017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04796-1https://doaj.org/toc/2045-2322Abstract 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/ITDneg 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.Jonathan MettsHeath L. BradleyZhengqi WangNeil P. ShahReuben KapurJack L. ArbiserKevin D. BuntingNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jonathan Metts Heath L. Bradley Zhengqi Wang Neil P. Shah Reuben Kapur Jack L. Arbiser Kevin D. Bunting Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
description	Abstract 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/ITDneg 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.
format	article
author	Jonathan Metts Heath L. Bradley Zhengqi Wang Neil P. Shah Reuben Kapur Jack L. Arbiser Kevin D. Bunting
author_facet	Jonathan Metts Heath L. Bradley Zhengqi Wang Neil P. Shah Reuben Kapur Jack L. Arbiser Kevin D. Bunting
author_sort	Jonathan Metts
title	Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
title_short	Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
title_full	Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
title_fullStr	Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
title_full_unstemmed	Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
title_sort	imipramine blue sensitively and selectively targets flt3-itd positive acute myeloid leukemia cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/194b5d0b84eb4fd8aa2867b88dfc9dc5
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Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells

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