Influence of arginine metabolites on human tumor cell viability upon arginine deprivation in vitro

In human organism arginine is necessary not only for protein synthesis but it also serves as a precursor for a number of important biologically active substances that influence cell growth and viability. These substances include such arginine metabolites as polyamines, nitric oxide, agmatine, ornithine and urea. It is known that in vitro tumor cells substantially differ in the level of sensitivity to arginine deprivation, which is reflected in the dynamics of apoptotic manifestations under these conditions. Identification of the molecular reasons of this phenomenon is important for optimization of the regimes of arginine deprivation-based anticancer enzymotherapy. One of possible reasons of the various level of sensitivity of tumor cells to arginine deprivation may reside in differences in their susceptibility to arginine catabolites withdrawal. Therefore, we aimed to investigate the effect of exogenous arginine metabolites (polyamines putrescine and spermine, as well as agmatine, nitric oxide, ornithine and urea) under arginine deprived conditions on viability and proliferative potential of two human cancer cell lines (A549 lung carcinoma and HepG2 hepatocarcinoma) that differ in the level of sensitivity to arginine depletion. It was revealed that none of the studied arginine catabolite affected cancer cell viability and proliferative potential in arginine-free medium, independently of the level of their sensitivity to arginine starvation. Thus, despite the complexity and versatility of arginine metabolic networks, the depletion of metabolites of this amino acid is not a key reason that determines differences in cell response to arginine deprivation. Therefore, identification of signaling mechanisms that underlie apoptosis induction in cancer cells upon arginine starvation needs to be further elucidated.