Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: Arginase as a potential drug candidate for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is auxotrophic for the semi-essential amino acid arginine, depletion of which leads to tumor death. In humans, arginine is not an essential amino acid since many adult somatic cells can re-synthesize it from other sources, such as citrulline. Enzymes capable of depleting arginine in vitro include the urea cycle enzyme arginase, which is found in abundance in human liver. For over three decades, arginase has not been considered as a potential drug candidate because of its low substrate affinity, short circulatory half-life and sub-optimal enzymatic activity at physiological pH, though its in vitro anti-tumor activities in certain tumors have been amply reported. Arginine deiminase, a bacterial enzyme from Mycoplasma hominus has been shown to induce HCC remission through the mechanism of arginine depletion. We report here an innovative treatment approach for the treatment of locally advanced and metastatic HCC with transhepatic arterial embolisation (TAE) of the liver tumor with lipiodol and gel foam as a means of inducing a leakage of hepatic arginase from the liver into the circulation. Hepatic arginase released into the systemic circulation rapidly depleted plasma arginine. High-dose insulin was included to induce a state of hypoaminoacidaemia to augment arginine depletion. With this protocol, we have treated seven patients with locally advanced and/or metastatic HCC. Five patients achieved arginine depletion, ranging from 0 to 20 μM (normal plasma level 100-120 μM); all had varying degrees of tumor remission in their primary tumors and extra-hepatic sites in the lymph nodes, lungs and bones, suggesting systemic anti-cancer effect of arginine depletion. The two non-responders did not show significant reduction in plasma arginine. Based on our findings, we propose that the urea cycle enzyme, arginase, is a good drug candidate for the treatment of HCC.