β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2
The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impede...
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doaj-c779deb6e9164deca14b94034a7902d12020-11-24T22:50:22ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-11-01910.3389/fphar.2018.01413423734β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2Haibo Cheng0Xiaoyin Ge1Shiqin Zhuo2Yanan Gao3Bo Zhu4Junfeng Zhang5Wenbin Shang6Dakang Xu7Dakang Xu8Dakang Xu9Weihong Ge10Liyun Shi11Liyun Shi12Collaborative Innovation Center of Cancer Prevention and Treatment, The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, ChinaSchool of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, ChinaCollaborative Innovation Center of Cancer Prevention and Treatment, The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, ChinaFaculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaKey Lab of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, ChinaHudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, AustraliaSchool of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, ChinaSchool of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, ChinaKey Lab of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, ChinaThe inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical application. β-elemene is a natural sesquiterpene with potent anti-cancer ability, and also it is renowned for its plant-origin, safety and the additive effect with traditional therapies, which prompt us to explore its potential to co-operate with TKIs to achieve greater therapeutic efficacy. Impressively, our study demonstrates that, elemene, in combination of gefitinib, displayed a significantly higher activity in inhibiting lung cancer cellular proliferation, migration and invasion. More importantly, combinative treatment profoundly impaired the epithelial to mesenchymal transition (EMT), the stem-like properties and the self-renewal capacity of lung cancer cells, and hence impeded the in vivo tumor development. We also reveal that the synergistic anti-tumor effect of elemene and gefitinib was largely mediated their regulation of enhancer of zeste homolog 2 (EZH2), an oncogenic histone methyltransferase and gene transcriptional regulator. Thus, our data indicate that combinative treatment of elemene and gefitinib has greater anti-neoplastic activity and greater efficacies in targeting cancer stem-like properties, mainly through regulating the malignant gene modifier and hence the subsequent effector molecules required for cancer progression. The findings may have potential implications for treating aggressive and resistant lung cancers.https://www.frontiersin.org/article/10.3389/fphar.2018.01413/fullelemenegefitiniblung cancerstemnessEZH2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Haibo Cheng Xiaoyin Ge Shiqin Zhuo Yanan Gao Bo Zhu Junfeng Zhang Wenbin Shang Dakang Xu Dakang Xu Dakang Xu Weihong Ge Liyun Shi Liyun Shi |
spellingShingle |
Haibo Cheng Xiaoyin Ge Shiqin Zhuo Yanan Gao Bo Zhu Junfeng Zhang Wenbin Shang Dakang Xu Dakang Xu Dakang Xu Weihong Ge Liyun Shi Liyun Shi β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 Frontiers in Pharmacology elemene gefitinib lung cancer stemness EZH2 |
author_facet |
Haibo Cheng Xiaoyin Ge Shiqin Zhuo Yanan Gao Bo Zhu Junfeng Zhang Wenbin Shang Dakang Xu Dakang Xu Dakang Xu Weihong Ge Liyun Shi Liyun Shi |
author_sort |
Haibo Cheng |
title |
β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 |
title_short |
β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 |
title_full |
β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 |
title_fullStr |
β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 |
title_full_unstemmed |
β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2 |
title_sort |
β-elemene synergizes with gefitinib to inhibit stem-like phenotypes and progression of lung cancer via down-regulating ezh2 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-11-01 |
description |
The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical application. β-elemene is a natural sesquiterpene with potent anti-cancer ability, and also it is renowned for its plant-origin, safety and the additive effect with traditional therapies, which prompt us to explore its potential to co-operate with TKIs to achieve greater therapeutic efficacy. Impressively, our study demonstrates that, elemene, in combination of gefitinib, displayed a significantly higher activity in inhibiting lung cancer cellular proliferation, migration and invasion. More importantly, combinative treatment profoundly impaired the epithelial to mesenchymal transition (EMT), the stem-like properties and the self-renewal capacity of lung cancer cells, and hence impeded the in vivo tumor development. We also reveal that the synergistic anti-tumor effect of elemene and gefitinib was largely mediated their regulation of enhancer of zeste homolog 2 (EZH2), an oncogenic histone methyltransferase and gene transcriptional regulator. Thus, our data indicate that combinative treatment of elemene and gefitinib has greater anti-neoplastic activity and greater efficacies in targeting cancer stem-like properties, mainly through regulating the malignant gene modifier and hence the subsequent effector molecules required for cancer progression. The findings may have potential implications for treating aggressive and resistant lung cancers. |
topic |
elemene gefitinib lung cancer stemness EZH2 |
url |
https://www.frontiersin.org/article/10.3389/fphar.2018.01413/full |
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