Cargando…
Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity
BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exc...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679490/ https://www.ncbi.nlm.nih.gov/pubmed/31375085 http://dx.doi.org/10.1186/s12885-019-5914-8 |
_version_ | 1783441347175251968 |
---|---|
author | Wang, Ning Fan, Yanhua Yuan, Chun-Mao Song, Jialei Yao, Yao Liu, Wuling Gajendran, Babu Zacksenhaus, Eldad Li, Yanmei Liu, Jielin Hao, Xiao Jiang Ben-David, Yaacov |
author_facet | Wang, Ning Fan, Yanhua Yuan, Chun-Mao Song, Jialei Yao, Yao Liu, Wuling Gajendran, Babu Zacksenhaus, Eldad Li, Yanmei Liu, Jielin Hao, Xiao Jiang Ben-David, Yaacov |
author_sort | Wang, Ning |
collection | PubMed |
description | BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541–43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS: Compounds A1541–43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541–43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541–43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541–43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541–43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5914-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6679490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66794902019-08-06 Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity Wang, Ning Fan, Yanhua Yuan, Chun-Mao Song, Jialei Yao, Yao Liu, Wuling Gajendran, Babu Zacksenhaus, Eldad Li, Yanmei Liu, Jielin Hao, Xiao Jiang Ben-David, Yaacov BMC Cancer Research Article BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541–43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS: Compounds A1541–43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541–43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541–43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541–43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541–43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5914-8) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-02 /pmc/articles/PMC6679490/ /pubmed/31375085 http://dx.doi.org/10.1186/s12885-019-5914-8 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Wang, Ning Fan, Yanhua Yuan, Chun-Mao Song, Jialei Yao, Yao Liu, Wuling Gajendran, Babu Zacksenhaus, Eldad Li, Yanmei Liu, Jielin Hao, Xiao Jiang Ben-David, Yaacov Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title | Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title_full | Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title_fullStr | Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title_full_unstemmed | Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title_short | Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity |
title_sort | selective erk1/2 agonists isolated from melia azedarach with potent anti-leukemic activity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679490/ https://www.ncbi.nlm.nih.gov/pubmed/31375085 http://dx.doi.org/10.1186/s12885-019-5914-8 |
work_keys_str_mv | AT wangning selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT fanyanhua selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT yuanchunmao selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT songjialei selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT yaoyao selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT liuwuling selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT gajendranbabu selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT zacksenhauseldad selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT liyanmei selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT liujielin selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT haoxiaojiang selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity AT bendavidyaacov selectiveerk12agonistsisolatedfrommeliaazedarachwithpotentantileukemicactivity |