Cargando…

Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway

Background and Purpose: Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from Cnidium monnieri (L.)...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Yun, Ren, Feng, Tian, Ziyin, Song, Wei, Cheng, Binfeng, Feng, Zhiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277458/
https://www.ncbi.nlm.nih.gov/pubmed/30538636
http://dx.doi.org/10.3389/fphar.2018.01392
_version_ 1783378155693670400
author Yang, Yun
Ren, Feng
Tian, Ziyin
Song, Wei
Cheng, Binfeng
Feng, Zhiwei
author_facet Yang, Yun
Ren, Feng
Tian, Ziyin
Song, Wei
Cheng, Binfeng
Feng, Zhiwei
author_sort Yang, Yun
collection PubMed
description Background and Purpose: Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson possesses potent anti-tumor activity. Here, we for the first time investigated the anti-tumor activity of trastuzumab in combination with osthole in HER2-overexpressing cancers. Materials and Methods: N87 and SK-BR-3 cell lines, which were HER2-overexpressing cancer cells were used in our study. Cell Counting Kit-8 (CCK-8) assay was utilized to test the inhibitory effects of trastuzumab plus osthole. Combination index (CI) values were calculated using the Chou-Talalay method. Fluorescence-Activated Cell Sorter (FACS) assay was used to examine the cell cycle change and apoptosis upon combinatorial treatment. N87 tumor xenografts were established to evaluate in vivo effects of trastuzumab plus osthole. In addition, molecular mechanisms were analyzed by Western blot in vitro and in vivo. Results: As shown in our study, osthole alone exhibited effective anti-tumor activity against HER2-overexpressed N87 gastric cancer cells and SK-BR-3 breast cancer cells, which may be attributed to cell cycle arrest on G2/M phase and apoptosis. More importantly, our data demonstrated that trastuzumab plus osthole was much more potent than either agent alone in inhibiting the growth of N87 cancer cells in vitro and in vivo, which may be partly explained by the enhanced apoptosis upon the combinatorial treatment. Besides these, we also observed a significant decrease on the phosphorylation of AKT and MAPK in N87 cells when treated with trastuzumab plus osthole compared to either agent alone. Further data from N87 tumor xenografts revealed that trastuzumab plus osthole exerted their synergistic effects mainly on AKT signaling pathway. Conclusion: Collectively, these results support the clinical development of combination osthole with trastuzumab for the treatment of HER2-overexpressed gastric cancer.
format Online
Article
Text
id pubmed-6277458
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-62774582018-12-11 Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway Yang, Yun Ren, Feng Tian, Ziyin Song, Wei Cheng, Binfeng Feng, Zhiwei Front Pharmacol Pharmacology Background and Purpose: Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson possesses potent anti-tumor activity. Here, we for the first time investigated the anti-tumor activity of trastuzumab in combination with osthole in HER2-overexpressing cancers. Materials and Methods: N87 and SK-BR-3 cell lines, which were HER2-overexpressing cancer cells were used in our study. Cell Counting Kit-8 (CCK-8) assay was utilized to test the inhibitory effects of trastuzumab plus osthole. Combination index (CI) values were calculated using the Chou-Talalay method. Fluorescence-Activated Cell Sorter (FACS) assay was used to examine the cell cycle change and apoptosis upon combinatorial treatment. N87 tumor xenografts were established to evaluate in vivo effects of trastuzumab plus osthole. In addition, molecular mechanisms were analyzed by Western blot in vitro and in vivo. Results: As shown in our study, osthole alone exhibited effective anti-tumor activity against HER2-overexpressed N87 gastric cancer cells and SK-BR-3 breast cancer cells, which may be attributed to cell cycle arrest on G2/M phase and apoptosis. More importantly, our data demonstrated that trastuzumab plus osthole was much more potent than either agent alone in inhibiting the growth of N87 cancer cells in vitro and in vivo, which may be partly explained by the enhanced apoptosis upon the combinatorial treatment. Besides these, we also observed a significant decrease on the phosphorylation of AKT and MAPK in N87 cells when treated with trastuzumab plus osthole compared to either agent alone. Further data from N87 tumor xenografts revealed that trastuzumab plus osthole exerted their synergistic effects mainly on AKT signaling pathway. Conclusion: Collectively, these results support the clinical development of combination osthole with trastuzumab for the treatment of HER2-overexpressed gastric cancer. Frontiers Media S.A. 2018-11-27 /pmc/articles/PMC6277458/ /pubmed/30538636 http://dx.doi.org/10.3389/fphar.2018.01392 Text en Copyright © 2018 Yang, Ren, Tian, Song, Cheng and Feng. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yang, Yun
Ren, Feng
Tian, Ziyin
Song, Wei
Cheng, Binfeng
Feng, Zhiwei
Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title_full Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title_fullStr Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title_full_unstemmed Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title_short Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway
title_sort osthole synergizes with her2 inhibitor, trastuzumab in her2-overexpressed n87 gastric cancer by inducing apoptosis and inhibition of akt-mapk pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277458/
https://www.ncbi.nlm.nih.gov/pubmed/30538636
http://dx.doi.org/10.3389/fphar.2018.01392
work_keys_str_mv AT yangyun ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway
AT renfeng ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway
AT tianziyin ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway
AT songwei ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway
AT chengbinfeng ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway
AT fengzhiwei ostholesynergizeswithher2inhibitortrastuzumabinher2overexpressedn87gastriccancerbyinducingapoptosisandinhibitionofaktmapkpathway