@article{2c1af19d39a24ae2abd33f3ba8bc4f23,
title = "Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer",
abstract = " Small cell lung cancer (SCLC) is a malignant neuroendocrine tumor with very high mortality. Effective new therapy for advanced SCLC patients is urgently needed. By screening a FDA-approved drug library, we identified a cardiac glycoside (CG), namely digoxin (an inhibitor of cellular Na + /K + ATPase pump), which was highly effective in inhibiting SCLC cell growth. Intriguing findings showed that NaCl supplement markedly enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na + and Ca 2+ levels with an induction of higher resting membrane potential of SCLC cells. We also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, our data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na + /K + ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, our study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na + is often present in SCLC patients.",
keywords = "ATP1A1, NaCl, cardiac glycosides, digoxin, small cell lung cancer",
author = "Ke Deng and Jiawei Shen and Wei Wang and Ming Li and Hong Li and Cheng Chen and Huan Zhao and Mei Zhang and Tian Xue and Qingsong Liu and Lui, {Vivian Wai Yan} and Bo Hong and Wenchu Lin",
note = "Funding Information: This work was supported by National Natural Science Foundation of China [81502632]; National Natural Science Foundation of China [81372214]; Natural Science Foundation of Anhui Province [1608085MH179]; Key Technologies R & D Program of Anhui Province [1604a0802103]; The Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology [2016FXCX006]; National Natural Science Foundation of China [31601134]; National Natural Science Foundation of China [61727811], Innovative program (ZT00102901), Natural Science Foundation of Anhui Province [1708085QC57]; Research Grant Council, Hong Kong [17114814]; Research Grant Council, Hong Kong [17121616]; Research Grant Council, Hong Kong [T12-401/13-R]. Funding Information: This work was supported by National Natural Science Foundation of China [81502632]; National Natural Science Foundation of China [81372214]; Natural Science Foundation of Anhui Province [1608085MH179]; Key Technologies R & D Program of Anhui Province [1604a0802103]; The Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology [2016FXCX006]; National Natural Science Foundation of China [31601134]; National Natural Science Foundation of China [61727811], Innovative program (ZT00102901), Natural Science Foundation of Anhui Province [1708085QC57]; Research Grant Council, Hong Kong [17114814]; Research Grant Council, Hong Kong [17121616]; Research Grant Council, Hong Kong [T12-401/13-R]. We thank Dr. Matthew Meyerson (Dana-Farber Cancer Institute, USA) for kindly providing SCLC cell lines. This study was supported by National Natural Science Foundation of China (Grant Numbers: 81502632 and 81372214), Natural Science Foundation of Anhui Province (Grant Number: 1608085MH179), Key Technologies R & D Program of Anhui Province (Grant Number: 1604a0802103), The Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (Grant Number: 2016FXCX006) and the 100-Talent Program of Chinese Academy of Sciences. VWYL is funded by the Research Grant Council, Hong Kong (#17114814, #17121616, General Research Fund), (Theme-based Research Scheme: T12-401/13-R), the Start-up Fund from the School of Biomedical Sciences, Direct Grant for Research (#2016.095) Faculty of Medicine, the Chinese University of Hong Kong. HZ was supported by National Natural Science Foundation of China (31601134, 61727811), Innovative program (ZT00102901), Natural Science Foundation of Anhui Province (1708085QC57) Funding Information: We thank Dr. Matthew Meyerson (Dana-Farber Cancer Institute, USA) for kindly providing SCLC cell lines. This study was supported by National Natural Science Foundation of China (Grant Numbers: 81502632 and 81372214), Natural Science Foundation of Anhui Province (Grant Number: 1608085MH179), Key Technologies R & D Program of Anhui Province (Grant Number: 1604a0802103), The Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (Grant Number: 2016FXCX006) and the 100-Talent Program of Chinese Academy of Sciences. VWYL is funded by the Research Grant Council, Hong Kong (#17114814, #17121616, General Research Fund), (Theme-based Research Scheme: T12-401/13-R), the Start-up Fund from the School of Biomedical Sciences, Direct Grant for Research (#2016.095) Faculty of Medicine, the Chinese University of Hong Kong. HZ was supported by National Natural Science Foundation of China (31601134, 61727811), Innovative program (ZT00102901), Natural Science Foundation of Anhui Province (1708085QC57) Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018 Taylor & Francis Group, LLC.",
year = "2019",
month = jan,
day = "2",
doi = "10.1080/15384047.2018.1504723",
language = "English (US)",
volume = "20",
pages = "52--64",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "1",
}