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Thioredoxin Reductase is a major regulator of metabolism in leukemia cells

Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR,...

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Autores principales: Karunanithi, Sheelarani, Liu, Ruifu, Hou, Yongchun, Gonzalez, Giancarlo, Oldford, Natasha, Roe, Anne Jessica, Idipilly, Nethrie, Gupta, Kalpana, Amara, Chandra Sekhar, Putluri, Satwikreddy, Lee, Grace Kyueun, Valentin-Goyco, Juan, Stetson, Lindsay, Moreton, Stephen A, Putluri, Vasanta, Kavuri, Shyam M, Saunthararajah, Yogen, de Lima, Marcos, Tochtrop, Gregory P, Putluri, Nagireddy, Wald, David N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380733/
https://www.ncbi.nlm.nih.gov/pubmed/34239044
http://dx.doi.org/10.1038/s41388-021-01924-0
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author Karunanithi, Sheelarani
Liu, Ruifu
Hou, Yongchun
Gonzalez, Giancarlo
Oldford, Natasha
Roe, Anne Jessica
Idipilly, Nethrie
Gupta, Kalpana
Amara, Chandra Sekhar
Putluri, Satwikreddy
Lee, Grace Kyueun
Valentin-Goyco, Juan
Stetson, Lindsay
Moreton, Stephen A
Putluri, Vasanta
Kavuri, Shyam M
Saunthararajah, Yogen
de Lima, Marcos
Tochtrop, Gregory P
Putluri, Nagireddy
Wald, David N
author_facet Karunanithi, Sheelarani
Liu, Ruifu
Hou, Yongchun
Gonzalez, Giancarlo
Oldford, Natasha
Roe, Anne Jessica
Idipilly, Nethrie
Gupta, Kalpana
Amara, Chandra Sekhar
Putluri, Satwikreddy
Lee, Grace Kyueun
Valentin-Goyco, Juan
Stetson, Lindsay
Moreton, Stephen A
Putluri, Vasanta
Kavuri, Shyam M
Saunthararajah, Yogen
de Lima, Marcos
Tochtrop, Gregory P
Putluri, Nagireddy
Wald, David N
author_sort Karunanithi, Sheelarani
collection PubMed
description Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.
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spelling pubmed-83807332022-01-08 Thioredoxin Reductase is a major regulator of metabolism in leukemia cells Karunanithi, Sheelarani Liu, Ruifu Hou, Yongchun Gonzalez, Giancarlo Oldford, Natasha Roe, Anne Jessica Idipilly, Nethrie Gupta, Kalpana Amara, Chandra Sekhar Putluri, Satwikreddy Lee, Grace Kyueun Valentin-Goyco, Juan Stetson, Lindsay Moreton, Stephen A Putluri, Vasanta Kavuri, Shyam M Saunthararajah, Yogen de Lima, Marcos Tochtrop, Gregory P Putluri, Nagireddy Wald, David N Oncogene Article Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism. 2021-07-08 2021-08 /pmc/articles/PMC8380733/ /pubmed/34239044 http://dx.doi.org/10.1038/s41388-021-01924-0 Text en https://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
spellingShingle Article
Karunanithi, Sheelarani
Liu, Ruifu
Hou, Yongchun
Gonzalez, Giancarlo
Oldford, Natasha
Roe, Anne Jessica
Idipilly, Nethrie
Gupta, Kalpana
Amara, Chandra Sekhar
Putluri, Satwikreddy
Lee, Grace Kyueun
Valentin-Goyco, Juan
Stetson, Lindsay
Moreton, Stephen A
Putluri, Vasanta
Kavuri, Shyam M
Saunthararajah, Yogen
de Lima, Marcos
Tochtrop, Gregory P
Putluri, Nagireddy
Wald, David N
Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title_full Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title_fullStr Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title_full_unstemmed Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title_short Thioredoxin Reductase is a major regulator of metabolism in leukemia cells
title_sort thioredoxin reductase is a major regulator of metabolism in leukemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380733/
https://www.ncbi.nlm.nih.gov/pubmed/34239044
http://dx.doi.org/10.1038/s41388-021-01924-0
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