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Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models
With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat can...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812272/ https://www.ncbi.nlm.nih.gov/pubmed/33274592 http://dx.doi.org/10.1111/jcmm.16132 |
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author | Caston, Rachel A. Shah, Fenil Starcher, Colton L. Wireman, Randall Babb, Olivia Grimard, Michelle McGeown, Jack Armstrong, Lee Tong, Yan Pili, Roberto Rupert, Joseph Zimmers, Teresa A. Elmi, Adily N. Pollok, Karen E. Motea, Edward A. Kelley, Mark R. Fishel, Melissa L. |
author_facet | Caston, Rachel A. Shah, Fenil Starcher, Colton L. Wireman, Randall Babb, Olivia Grimard, Michelle McGeown, Jack Armstrong, Lee Tong, Yan Pili, Roberto Rupert, Joseph Zimmers, Teresa A. Elmi, Adily N. Pollok, Karen E. Motea, Edward A. Kelley, Mark R. Fishel, Melissa L. |
author_sort | Caston, Rachel A. |
collection | PubMed |
description | With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref‐1 is a multifunctional protein with a role in redox signalling that activates transcription factors such as NF‐κB, AP‐1, HIF‐1α and STAT3. Formerly, we have demonstrated that dual targeting of Ref‐1 (redox factor‐1) and STAT3 is synergistic and decreases cell viability in pancreatic cancer cells. Data presented here extensively expands upon this work and provides further insights into the relationship of STAT3 and Ref‐1 in multiple cancer types. Using targeted small molecule inhibitors, Ref‐1 redox signalling was blocked along with STAT3 activation, and tumour growth evaluated in the presence and absence of the relevant tumour microenvironment. Our study utilized qPCR, cytotoxicity and in vivo analysis of tumour and cancer‐associated fibroblasts (CAF) response to determine the synergy of Ref‐1 and STAT3 inhibitors. Overall, pancreatic tumours grown in the presence of CAFs were sensitized to the combination of STAT3 and Ref‐1 inhibition in vivo. In vitro bladder and pancreatic cancer demonstrated the most synergistic responses. By disabling both of these important pathways, this combination therapy has the capacity to hinder crosstalk between the tumour and its microenvironment, leading to improved tumour response. |
format | Online Article Text |
id | pubmed-7812272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78122722021-01-22 Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models Caston, Rachel A. Shah, Fenil Starcher, Colton L. Wireman, Randall Babb, Olivia Grimard, Michelle McGeown, Jack Armstrong, Lee Tong, Yan Pili, Roberto Rupert, Joseph Zimmers, Teresa A. Elmi, Adily N. Pollok, Karen E. Motea, Edward A. Kelley, Mark R. Fishel, Melissa L. J Cell Mol Med Original Articles With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref‐1 is a multifunctional protein with a role in redox signalling that activates transcription factors such as NF‐κB, AP‐1, HIF‐1α and STAT3. Formerly, we have demonstrated that dual targeting of Ref‐1 (redox factor‐1) and STAT3 is synergistic and decreases cell viability in pancreatic cancer cells. Data presented here extensively expands upon this work and provides further insights into the relationship of STAT3 and Ref‐1 in multiple cancer types. Using targeted small molecule inhibitors, Ref‐1 redox signalling was blocked along with STAT3 activation, and tumour growth evaluated in the presence and absence of the relevant tumour microenvironment. Our study utilized qPCR, cytotoxicity and in vivo analysis of tumour and cancer‐associated fibroblasts (CAF) response to determine the synergy of Ref‐1 and STAT3 inhibitors. Overall, pancreatic tumours grown in the presence of CAFs were sensitized to the combination of STAT3 and Ref‐1 inhibition in vivo. In vitro bladder and pancreatic cancer demonstrated the most synergistic responses. By disabling both of these important pathways, this combination therapy has the capacity to hinder crosstalk between the tumour and its microenvironment, leading to improved tumour response. John Wiley and Sons Inc. 2020-12-03 2021-01 /pmc/articles/PMC7812272/ /pubmed/33274592 http://dx.doi.org/10.1111/jcmm.16132 Text en © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Caston, Rachel A. Shah, Fenil Starcher, Colton L. Wireman, Randall Babb, Olivia Grimard, Michelle McGeown, Jack Armstrong, Lee Tong, Yan Pili, Roberto Rupert, Joseph Zimmers, Teresa A. Elmi, Adily N. Pollok, Karen E. Motea, Edward A. Kelley, Mark R. Fishel, Melissa L. Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title | Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title_full | Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title_fullStr | Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title_full_unstemmed | Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title_short | Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models |
title_sort | combined inhibition of ref‐1 and stat3 leads to synergistic tumour inhibition in multiple cancers using 3d and in vivo tumour co‐culture models |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812272/ https://www.ncbi.nlm.nih.gov/pubmed/33274592 http://dx.doi.org/10.1111/jcmm.16132 |
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