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Molecules 2016, 21(3), 374; doi:10.3390/molecules21030374

Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation

1
State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR, China
2
Department of Thoracic Surgery, The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou 510120, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 5 January 2016 / Revised: 14 March 2016 / Accepted: 15 March 2016 / Published: 18 March 2016
(This article belongs to the Collection Herbal Medicine Research)
View Full-Text   |   Download PDF [2964 KB, uploaded 18 March 2016]   |  

Abstract

Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5′ adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest. View Full-Text
Keywords: natural product compound library; Digitoxin; NSCLC; EGFR; TKI resistance; microtubule; cell cycle; α-tubulin natural product compound library; Digitoxin; NSCLC; EGFR; TKI resistance; microtubule; cell cycle; α-tubulin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Zhang, Y.-Z.; Chen, X.; Fan, X.-X.; He, J.-X.; Huang, J.; Xiao, D.-K.; Zhou, Y.-L.; Zheng, S.-Y.; Xu, J.-H.; Yao, X.-J.; Liu, L.; Leung, E.L.-H. Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation. Molecules 2016, 21, 374.

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