BOOSTING THE INCREASE OF INTRACELLULAR SODIUM TO KILL SELECTIVELY HEPATIC CANCER CELLS: PRECLINICAL PROOF OF CONCEPT

Background Aerobic glycolytic metabolism and intracellular alkaline pH with concomitant extracellular acidosis are hallmarks of cancer. The reverse pH gradient compared with healthy tissue relies on the increased activity or expression of pH regulatory proteins and, among them, of Na+ transporters. In previous studies with non-cancerous cells, we showed that an irreversible increase of intracellular Na+ precedes death following ATP depletion and it is the final cause of the osmotic lysis and death of primary hepatocytes. We have also shown that intrinsic hepato-protection by ischemic preconditioning involves an increased resistance of hepatocyte to hypoxic damage due to prevention of intracellular Na+ overload. The significance of Na+ intracellular variations in cancer cell metabolism, growth and viability is, to date, unknown. Early X ray microanalysis of rodent cells and recent MRI studies of human cancers evidence, however, an augmented intracellular concentration of Na+ in cancer cells in comparison to healthy cells. Moreover, "in vivo Field-Cycling Relaxometry" studies demonstrate a significantly enhanced water exchange of cancer cells that is indicative of an increased intracellular osmotic pressure in tumors. Hypothesis We hypothesize that cancer cells, owing to a constitutively high intracellular Na+ concentration and high energy-consuming metabolism, are energetically unable to compensate and survive to a further Na+ load. Consistently, our preliminary experiments show that the Na+ ionophore monensin selectively kills "in vitro" hepatoma cells but not primary hepatocytes and blocks "in vivo" growth of xenogenic hepatic tumors in -null mice, inducing an extensive necrosis of tumours yet not affecting healthy tissues.