Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Ke Deng; Jiawei Shen; Wei Wang; Ming Li; Hong Li; Cheng Chen; Huan Zhao; Mei Zhang; Tian Xue; Qingsong Liu; Vivian Wai Yan Lui; Bo Hong; Wenchu Lin

doi:10.1080/15384047.2018.1504723

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

Cancer Biol Ther. 2019;20(1):52-64. doi: 10.1080/15384047.2018.1504723. Epub 2018 Sep 5.

Authors

Ke Deng^{1

2

3}, Jiawei Shen⁴, Wei Wang^{1

3}, Ming Li^{1

2

3

5}, Hong Li^{1

3}, Cheng Chen^{1

2

3}, Huan Zhao⁴, Mei Zhang⁴, Tian Xue⁴, Qingsong Liu^{1

3}, Vivian Wai Yan Lui⁶, Bo Hong^{1

3}, Wenchu Lin^{1

3}

Affiliations

¹ a High Magnetic Field Laboratory , Chinese Academy of Sciences , Hefei , P. R. China.
² b University of Science and Technology of China , Hefei , P. R. China.
³ c Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science , Chinese Academy of Sciences , Hefei , P. R. China.
⁴ d School of Life Sciences , University of Science and Technology of China , Hefei , P. R. China.
⁵ e Department of Laboratory Diagnostics , Western Branch of The First Affiliated Hospital of University of Science and Technology of China , Hefei , P. R. China.
⁶ f School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR.

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 Ca²⁺ 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Line, Tumor
Digoxin / pharmacology*
Digoxin / therapeutic use
Drug Screening Assays, Antitumor
Drug Synergism
High-Throughput Screening Assays
Humans
Lung Neoplasms / blood
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Membrane Potentials / drug effects
Small Cell Lung Carcinoma / blood
Small Cell Lung Carcinoma / drug therapy*
Small Cell Lung Carcinoma / pathology
Sodium / blood
Sodium Chloride / pharmacology*
Sodium Chloride / therapeutic use
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors

Substances

Sodium Chloride
Digoxin
Sodium
ATP1A1 protein, human
Sodium-Potassium-Exchanging ATPase

Grants and funding

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].