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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,...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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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. |
format | Online Article Text |
id | pubmed-8380733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
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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