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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)52-64
Number of pages13
JournalCancer Biology and Therapy
Volume20
Issue number1
DOIs
StatePublished - Jan 2 2019
Externally publishedYes

Keywords

  • ATP1A1
  • NaCl
  • cardiac glycosides
  • digoxin
  • small cell lung cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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