Sodium and water fluxes as biomarkers for cancer diagnosis and therapy in monensin treated hepatocellular carcinoma.

This study aimed to explore the role and potential of 1H Nuclear Magnetic Resonance (NMR) relaxometry and 23Na Magnetic resonance Imaging (MRI) as effective tools for monitoring water fluxes and dysregulation of Na+ homeostasis in cancer cells, considered as novel target for therapeutic intervention. The effect of a forced Na+ influx induced by the ionophore Monensin on hepatocellular carcinoma (HCC) models was compared with that on hepatocytes (HPs) and other healthy tissues. Monensin is a polyether ionophore which is able to reversibly bind Na+ and facilitate its transport across the cellular membrane along concentration gradient. Na+ levels and water fluxes were assessed with ICP-MS, 23Na-MRI and NMR relaxometry, and showed that HCC cells exhibited higher Na+ intracellular concentration compared to HPs and other healthy tissue and that treatment with Monensin further increased Na+ levels in HCC cells and HCC allografts. On the contrary, the treatment did not affect HPs and normal hepatic, extrahepatic tissue and organs. The treatment, with its forced increase of Na+, also led to a reduction of the water efflux rate in HCC cells evaluated by 1H NMR relaxometry, reflecting reduced tumor aggressiveness as confirmed by the regression of allograft tumors and necrosis observed with 23Na-MRI. The results reported herein suggest that 1H NMR relaxometry and 23Na-MRI are effective diagnostic tools for the assessment of water fluxes and Na+ as new biomarkers for cancer and therapy. Furthermore, the pharmacologically induced Na+ overload, which strongly affected HCC cells and not healthy tissues, suggests that Na+ homeostasis represents an unexplored and efficace target for HCC therapy.