INHIBITION OF THE GROWTH OF TRANSFORMED AND NEOPLASTIC-CELLS BY THE DIPEPTIDE CARNOSINE

Human diploid fibroblasts grow normally in medium containing physiolog ical concentrations of the naturally occurring dipeptide carnosine (be ta-alanyl-L-histidine). These concentrations are cytotoxic to transfor med and neoplastic cells lines in modified Eagle medium (MEM), whereas these cells grow vigorously in Dulbecco's modified Eagle medium (DMEM ) containing carnosine. This difference is due to the presence of 1 mM sodium pyruvate in DMEM. Seven human cell lines and two rodent cell l ines were tested and all are strongly inhibited by carnosine in the ab sence of pyruvate. Experiments with HeLa cells show that anserine is s imilar to carnosine, but D-carnosine and homocarnosine are without eff ect. Also, the non-essential amino acids alanine and glutamic acid con tribute to the effect of pyruvate in preventing carnosine toxicity, an d oxaloacetate and alpha-ketoglutarate can substitute for pyruvate. We have used mixtures of normal MRC-5 fibroblasts and HeLa cells to demo nstrate that 20 mM carnosine can selectively eliminate the tumour cell s. This has obvious implications which might be exploited in in vivo a nd in vitro studies. Carnosine is known to react strongly with aldehyd e and keto groups of sugars by the Amadori reaction, and we propose th at it depletes certain glycolysis intermediates. It is well known that tumour cells are more dependent on glycolysis than normal cells. A re duction of glycolysis intermediates by carnosine may deplete their ene rgy supply, but this effect is totally reversed by pyruvate.