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Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis

SIMPLE SUMMARY: We used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the eff...

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Autores principales: Robinson, Prema, Montoya, Kelsey, Magness, Emily, Rodriguez, Emma, Villalobos, Viviana, Engineer, Nikita, Yang, Peng, Bharadwaj, Uddalak, Eckols, Thomas Kris, Tweardy, David John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10251885/
https://www.ncbi.nlm.nih.gov/pubmed/37296943
http://dx.doi.org/10.3390/cancers15112977
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author Robinson, Prema
Montoya, Kelsey
Magness, Emily
Rodriguez, Emma
Villalobos, Viviana
Engineer, Nikita
Yang, Peng
Bharadwaj, Uddalak
Eckols, Thomas Kris
Tweardy, David John
author_facet Robinson, Prema
Montoya, Kelsey
Magness, Emily
Rodriguez, Emma
Villalobos, Viviana
Engineer, Nikita
Yang, Peng
Bharadwaj, Uddalak
Eckols, Thomas Kris
Tweardy, David John
author_sort Robinson, Prema
collection PubMed
description SIMPLE SUMMARY: We used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. We demonstrated that DSS-induced colitis is more severe in mice that express only STAT3α compared to wild-type mice and that administration of TTI-101 completely prevented DSS-induced colitis as well as reversed upregulation of CRC-associated genes. ABSTRACT: Background and Aims: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. Methods: We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. Results: Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. Conclusions: Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
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spelling pubmed-102518852023-06-10 Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis Robinson, Prema Montoya, Kelsey Magness, Emily Rodriguez, Emma Villalobos, Viviana Engineer, Nikita Yang, Peng Bharadwaj, Uddalak Eckols, Thomas Kris Tweardy, David John Cancers (Basel) Article SIMPLE SUMMARY: We used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. We demonstrated that DSS-induced colitis is more severe in mice that express only STAT3α compared to wild-type mice and that administration of TTI-101 completely prevented DSS-induced colitis as well as reversed upregulation of CRC-associated genes. ABSTRACT: Background and Aims: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. Methods: We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. Results: Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. Conclusions: Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer. MDPI 2023-05-30 /pmc/articles/PMC10251885/ /pubmed/37296943 http://dx.doi.org/10.3390/cancers15112977 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Robinson, Prema
Montoya, Kelsey
Magness, Emily
Rodriguez, Emma
Villalobos, Viviana
Engineer, Nikita
Yang, Peng
Bharadwaj, Uddalak
Eckols, Thomas Kris
Tweardy, David John
Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title_full Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title_fullStr Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title_full_unstemmed Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title_short Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
title_sort therapeutic potential of a small-molecule stat3 inhibitor in a mouse model of colitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10251885/
https://www.ncbi.nlm.nih.gov/pubmed/37296943
http://dx.doi.org/10.3390/cancers15112977
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