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

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.

A RANKL Wrinkle: Denosumab-Induced Hypocalcemia.

The human monoclonal antibody denosumab inhibits osteoclast-mediated bone resorption by binding to receptor activator of nuclear factor κB ligand (RANKL), which is upregulated by tumor cells. Denosumab is indicated to prevent skeletal-related events (SREs) from osteoporosis and metastatic bone disease. We report a case of denosumab-induced hypocalcemia to highlight potential toxicity and treatment considerations. A 66-year-old man with prostate cancer, small cell lung cancer, and bone metastases presented with fatigue, weakness, and muscle spasm. Sixteen days prior, he received cycle 6 of cisplatin and etoposide, leuprolide, and denosumab (120 mg subcutaneously). His examination demonstrated a slight resting tremor, normal strength, and negative Chvostek sign. Laboratory analysis revealed hemoglobin, 8.0 g/dL; total calcium, 5.2 mg/dL (pre-denosumab, 8.9 mg/dL); and magnesium, 0.7 mg/dL. He initially received two units packed red blood cells, intravenous calcium and magnesium, and vitamin D. During his hospitalization, he required multiple doses of intravenous and oral calcium, magnesium, and vitamin D. Despite ongoing oral supplementation, his post-discharge serum calcium fluctuated significantly, requiring close monitoring and frequent dose adjustments. Denosumab's unique antiresorptive properties yield fewer SREs. The trade-off is increased hypocalcemia risk, which may be severe and require aggressive, prolonged supplementation and monitoring.

Is there any potential clinical impact of serum phosphorus and magnesium in patients with lung cancer at first diagnosis? A multi-institutional study.

BACKGROUND: The aim of the study was to determine whether the expression of baseline phosphorus (P) and magnesium (Mg) levels were prognostic in terms of stage and overall survival (OS) in newly diagnosed non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients. MATERIALS AND METHODS: Retrospectively, 130 patients were selected at the time of diagnosis oflung cancer (100 with NSCLC and 30 with SCLC), before the initialization of any chemo-radiotherapy. The median age was 67 (range 29-92). IA, IB, IIA, IIB, IIIA, IIIB and IV stages were present in 3, 4, 19, 6, 25, 8, and 65 patients, respectively. After centrifugation, the levels of serum P and Mg were measured using the nephelometric method/ photometry and evaluated before any type of treatment. RESULTS: Higher than normal levels of P were found in 127/130 patients, while only four patients had elevated Mg serum values. In terms of Spearman test, higher P serum values correlated with either stage (rho=- 0.334, p<0.001) or OS (rho=-0.212, p=0.016). Additionally, a significant negative correlation of Mg serum levels was found with stage of disease (rho=-0.135, P=0.042). On multivariate cox-regression survival analysis, only stage (p<0.01), performance status (p<0.01) and P serum (p=0.045) showed a significant prognostic value. CONCLUSIONS: Our study indicated that pre-treatment P serum levels in lung cancer patients are higher than the normal range. Moreover, P and Mg serum levels are predictive of stage of disease. Along with stage and performance status, the P serum levels had also a significant impact on survival. This information may be important for stratifying patients to specific treatment protocols or intensifying their therapies. However, larger series are now needed to confirm our results.