Cargando…
Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis
A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroi...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782168/ https://www.ncbi.nlm.nih.gov/pubmed/36558080 http://dx.doi.org/10.3390/molecules27248948 |
_version_ | 1784857276419407872 |
---|---|
author | Iksen, Iksen Sinsook, Suwimon Wattanathamsan, Onsurang Buaban, Koonchira Chamni, Supakarn Pongrakhananon, Varisa |
author_facet | Iksen, Iksen Sinsook, Suwimon Wattanathamsan, Onsurang Buaban, Koonchira Chamni, Supakarn Pongrakhananon, Varisa |
author_sort | Iksen, Iksen |
collection | PubMed |
description | A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds. |
format | Online Article Text |
id | pubmed-9782168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97821682022-12-24 Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis Iksen, Iksen Sinsook, Suwimon Wattanathamsan, Onsurang Buaban, Koonchira Chamni, Supakarn Pongrakhananon, Varisa Molecules Article A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds. MDPI 2022-12-15 /pmc/articles/PMC9782168/ /pubmed/36558080 http://dx.doi.org/10.3390/molecules27248948 Text en © 2022 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 Iksen, Iksen Sinsook, Suwimon Wattanathamsan, Onsurang Buaban, Koonchira Chamni, Supakarn Pongrakhananon, Varisa Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title | Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title_full | Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title_fullStr | Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title_full_unstemmed | Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title_short | Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis |
title_sort | target identification of 22-(4-pyridinecarbonyl) jorunnamycin a, a tetrahydroisoquinoline derivative from the sponge xestospongia sp., in mediating non-small-cell lung cancer cell apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782168/ https://www.ncbi.nlm.nih.gov/pubmed/36558080 http://dx.doi.org/10.3390/molecules27248948 |
work_keys_str_mv | AT ikseniksen targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis AT sinsooksuwimon targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis AT wattanathamsanonsurang targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis AT buabankoonchira targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis AT chamnisupakarn targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis AT pongrakhananonvarisa targetidentificationof224pyridinecarbonyljorunnamycinaatetrahydroisoquinolinederivativefromthespongexestospongiaspinmediatingnonsmallcelllungcancercellapoptosis |