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Drug Repurposing to Treat Glucocorticoid Resistance in Asthma

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Progra...

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Autores principales: Wang, Alberta L., Panganiban, Ronald, Qiu, Weiliang, Kho, Alvin T., Chupp, Geoffrey, Meyers, Deborah A., Bleecker, Eugene R., Weiss, Scott T., Lu, Quan, Tantisira, Kelan G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999884/
https://www.ncbi.nlm.nih.gov/pubmed/33802355
http://dx.doi.org/10.3390/jpm11030175
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author Wang, Alberta L.
Panganiban, Ronald
Qiu, Weiliang
Kho, Alvin T.
Chupp, Geoffrey
Meyers, Deborah A.
Bleecker, Eugene R.
Weiss, Scott T.
Lu, Quan
Tantisira, Kelan G.
author_facet Wang, Alberta L.
Panganiban, Ronald
Qiu, Weiliang
Kho, Alvin T.
Chupp, Geoffrey
Meyers, Deborah A.
Bleecker, Eugene R.
Weiss, Scott T.
Lu, Quan
Tantisira, Kelan G.
author_sort Wang, Alberta L.
collection PubMed
description Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV(1)). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV(1), to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.
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spelling pubmed-79998842021-03-28 Drug Repurposing to Treat Glucocorticoid Resistance in Asthma Wang, Alberta L. Panganiban, Ronald Qiu, Weiliang Kho, Alvin T. Chupp, Geoffrey Meyers, Deborah A. Bleecker, Eugene R. Weiss, Scott T. Lu, Quan Tantisira, Kelan G. J Pers Med Article Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV(1)). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV(1), to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics. MDPI 2021-03-03 /pmc/articles/PMC7999884/ /pubmed/33802355 http://dx.doi.org/10.3390/jpm11030175 Text en © 2021 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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Wang, Alberta L.
Panganiban, Ronald
Qiu, Weiliang
Kho, Alvin T.
Chupp, Geoffrey
Meyers, Deborah A.
Bleecker, Eugene R.
Weiss, Scott T.
Lu, Quan
Tantisira, Kelan G.
Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title_full Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title_fullStr Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title_full_unstemmed Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title_short Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
title_sort drug repurposing to treat glucocorticoid resistance in asthma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999884/
https://www.ncbi.nlm.nih.gov/pubmed/33802355
http://dx.doi.org/10.3390/jpm11030175
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