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Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies
Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chines...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689587/ https://www.ncbi.nlm.nih.gov/pubmed/29156697 http://dx.doi.org/10.18632/oncotarget.17761 |
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author | Lu, Zheng Lai, Zheng-Quan Leung, Albert W.N. Leung, Po Sing Li, Zhao-Shen Lin, Zhi-Xiu |
author_facet | Lu, Zheng Lai, Zheng-Quan Leung, Albert W.N. Leung, Po Sing Li, Zhao-Shen Lin, Zhi-Xiu |
author_sort | Lu, Zheng |
collection | PubMed |
description | Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile. In addition, brusatol showed a synergistic anti-proliferative effect toward PANC-1 and Capan-2 cell lines when combined with gemcitabine or 5-fluorouracil. The results of flow cytometry suggested that brusatol combination treatment with gemcitabine or 5-fluorouracil was able to cause cell cycle arrest at G2/M phase, and accentuate apoptosis in PANC-1 cells. Moreover, brusatol deactivated gemcitabine/5-fluorouracil-induced NF-κB activation. Western blot analysis and qRT-PCR results showed that brusatol significantly down-regulated the expression of vimentin and Twist, and markedly stimulated the expression of E-cadherin, the key regulatory factors of the epithelial-mesenchymal transition process. Furthermore, treatment with combination of brusatol and gemcitabine or 5-fluorouracil significantly reduced in vivo tumor growth when compared with treatment of either brusatol or gemcitabine/5-fluorouracil alone. Taken together, these results have amply demonstrated that brusatol is a potent anti-pancreatic cancer natural compound, and the synergistic anti-pancreatic cancer effects of brusatol and gemcitabine/5-fluorouracil observed both in vitro and in vivo are associated with the suppression of epithelial-mesenchymal transition process, indicating that brusatol is a promising adjunct to the current chemotherapeutic regimen. |
format | Online Article Text |
id | pubmed-5689587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56895872017-11-17 Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies Lu, Zheng Lai, Zheng-Quan Leung, Albert W.N. Leung, Po Sing Li, Zhao-Shen Lin, Zhi-Xiu Oncotarget Research Paper Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile. In addition, brusatol showed a synergistic anti-proliferative effect toward PANC-1 and Capan-2 cell lines when combined with gemcitabine or 5-fluorouracil. The results of flow cytometry suggested that brusatol combination treatment with gemcitabine or 5-fluorouracil was able to cause cell cycle arrest at G2/M phase, and accentuate apoptosis in PANC-1 cells. Moreover, brusatol deactivated gemcitabine/5-fluorouracil-induced NF-κB activation. Western blot analysis and qRT-PCR results showed that brusatol significantly down-regulated the expression of vimentin and Twist, and markedly stimulated the expression of E-cadherin, the key regulatory factors of the epithelial-mesenchymal transition process. Furthermore, treatment with combination of brusatol and gemcitabine or 5-fluorouracil significantly reduced in vivo tumor growth when compared with treatment of either brusatol or gemcitabine/5-fluorouracil alone. Taken together, these results have amply demonstrated that brusatol is a potent anti-pancreatic cancer natural compound, and the synergistic anti-pancreatic cancer effects of brusatol and gemcitabine/5-fluorouracil observed both in vitro and in vivo are associated with the suppression of epithelial-mesenchymal transition process, indicating that brusatol is a promising adjunct to the current chemotherapeutic regimen. Impact Journals LLC 2017-05-10 /pmc/articles/PMC5689587/ /pubmed/29156697 http://dx.doi.org/10.18632/oncotarget.17761 Text en Copyright: © 2017 Lu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Lu, Zheng Lai, Zheng-Quan Leung, Albert W.N. Leung, Po Sing Li, Zhao-Shen Lin, Zhi-Xiu Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title | Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title_full | Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title_fullStr | Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title_full_unstemmed | Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title_short | Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
title_sort | exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689587/ https://www.ncbi.nlm.nih.gov/pubmed/29156697 http://dx.doi.org/10.18632/oncotarget.17761 |
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