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Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer
Yang, Zheng1; Zhang, Shao-Lin1; Hu, Xiaohui2; Tam, Kin Yip1
2018-11-05
Source PublicationEUROPEAN JOURNAL OF PHARMACOLOGY
ISSN0014-2999
Volume838Pages:41-52
Abstract

Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired-resistance inevitably occurs after long-term exposure to the treatment of EGFR inhibitors. Glycolysis is a predominant process for most cancer cells to utilize glucose, which referred to as the Warburg Effect. Targeting critical enzymes, such as pyruvate dehydrogenase kinase 1 (PDK1) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. The purpose of this study is to evaluate whether PDK1 inhibition could enhance the anti-cancer effects of EGFR-TKi. Herein, we utilized a recently reported PDK1 inhibitor 2,2-Dichloro-1-(4-isopropoxy-3-nitrophenyl)ethan-1-one (Cpd64), which was more potent and selective than dichloroacetate (DCA) and/or dichloroacetophenone (DAP), to study the mechanism of PDK1 inhibition in TKi-mediated anti-cancer activity. We found that the introduction of Cpd64 in EGFR-TKi therapy enhanced the anti-proliferative effects in EGFR-mutant NSCLC cells under hypoxia. In particular, Cpd64 was shown to increase the activity of pyruvate dehydrogenase (PDH) and improved XPHOS, such as elevated mitochondrial respiration, and increased ATP generation, which effectively modulated the upregulation of PDK1 by EGFR-TKi treatment. We have observed that Cpd64 effectively enhanced the tumor growth inhibition induced by erlotinib in a NCI-H1975 xenograft mouse model. Collectively, our results suggested that combined use of selective PDK inhibitor and EGFR-TKi could be a potential strategy for NSCLC therapy.

KeywordDichloroacetophenone Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Synergism Hypoxia Oxidative Phosphorylation
DOI10.1016/j.ejphar.2018.09.016
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000445661900005
PublisherELSEVIER SCIENCE BV
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
2.Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
First Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Yang, Zheng,Zhang, Shao-Lin,Hu, Xiaohui,et al. Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2018,838:41-52.
APA Yang, Zheng,Zhang, Shao-Lin,Hu, Xiaohui,&Tam, Kin Yip.(2018).Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer.EUROPEAN JOURNAL OF PHARMACOLOGY,838,41-52.
MLA Yang, Zheng,et al."Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer".EUROPEAN JOURNAL OF PHARMACOLOGY 838(2018):41-52.
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