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 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.

Positive Inotropic Agents in Cancer Therapy: Exploring Potential Anti-Tumor Effects

“…Digoxin, known for its role as a cardioprotective drug due to its inhibition of Na + /K + -ATPase, hence promoting the intracellular accumulation of Ca 2+ ions, has also garnered attention for its potential anticancer properties [31,40,[72][73][74][75][76]. Interest in the relationship between cardiac glycosides (CGs) and cancer began to grow in the late 1970s due to two key discoveries.…”

“…In small cell lung cancer (SCLC), six cell lines were subjected to digoxin treatment, all exhibiting high sensitivity with rather low IC50 values (approximately 50 nM). It was identified that digoxin treatment alone induced cell cycle arrest in the G2 or M phase and triggered apoptosis across these cell lines [76].…”

Bioactive C21 Steroidal Glycosides from Euphorbia kansui Promoted HepG2 Cell Apoptosis via the Degradation of ATP1A1 and Inhibited Macrophage Polarization under Co-Cultivation

“…Therefore, ATP1A1 is a potential target for the treatment of HCC. Cardenolides, as NAK inhibitors, have been used in antitumor clinical research [ 13 , 14 ]. Even though it is a structurally similar compound, the notion as to whether C21 steroidal glycosides have an antitumor effect on NAK has not yet been reported [ 15 ].…”