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Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth

INTRODUCTION: Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa...

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Autores principales: Ma, Wen‐Lung, Chang, Ning, Yu, Yingchun, Su, Yu‐Ting, Chen, Guan‐Yu, Cheng, Wei‐Chung, Wu, Yang‐Chang, Li, Ching‐Chia, Chang, Wei‐Chun, Yang, Juan‐Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302273/
https://www.ncbi.nlm.nih.gov/pubmed/35545835
http://dx.doi.org/10.1002/cam4.4536
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author Ma, Wen‐Lung
Chang, Ning
Yu, Yingchun
Su, Yu‐Ting
Chen, Guan‐Yu
Cheng, Wei‐Chung
Wu, Yang‐Chang
Li, Ching‐Chia
Chang, Wei‐Chun
Yang, Juan‐Cheng
author_facet Ma, Wen‐Lung
Chang, Ning
Yu, Yingchun
Su, Yu‐Ting
Chen, Guan‐Yu
Cheng, Wei‐Chung
Wu, Yang‐Chang
Li, Ching‐Chia
Chang, Wei‐Chun
Yang, Juan‐Cheng
author_sort Ma, Wen‐Lung
collection PubMed
description INTRODUCTION: Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. METHOD: The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. RESULT: The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements.
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spelling pubmed-93022732022-07-22 Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth Ma, Wen‐Lung Chang, Ning Yu, Yingchun Su, Yu‐Ting Chen, Guan‐Yu Cheng, Wei‐Chung Wu, Yang‐Chang Li, Ching‐Chia Chang, Wei‐Chun Yang, Juan‐Cheng Cancer Med RESEARCH ARTICLES INTRODUCTION: Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. METHOD: The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. RESULT: The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements. John Wiley and Sons Inc. 2022-05-11 /pmc/articles/PMC9302273/ /pubmed/35545835 http://dx.doi.org/10.1002/cam4.4536 Text en © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle RESEARCH ARTICLES
Ma, Wen‐Lung
Chang, Ning
Yu, Yingchun
Su, Yu‐Ting
Chen, Guan‐Yu
Cheng, Wei‐Chung
Wu, Yang‐Chang
Li, Ching‐Chia
Chang, Wei‐Chun
Yang, Juan‐Cheng
Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title_full Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title_fullStr Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title_full_unstemmed Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title_short Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth
title_sort ursolic acid silences cyp19a1/aromatase to suppress gastric cancer growth
topic RESEARCH ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302273/
https://www.ncbi.nlm.nih.gov/pubmed/35545835
http://dx.doi.org/10.1002/cam4.4536
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