Metabolic pathways of L-arginine and therapeutic consequences in tumors

Abstract

Difference in the metabolism of normal and cancer cells inspires to search for new, more specific and less toxic therapies than those currently used. The development of tumors is conditioned by genetic changes in cancer-transformed cells, immunological tolerance and immunosuppression. At the initial stages of carcinogenesis, the immune system shows anti-tumor activity, however later, cancer disrupts the function of Th1/Th17/Th2 lymphocytes by regulatory T (Treg) cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) and finally causes immunosuppression. Recently, much attention has been devoted to the influence of l-arginine metabolism disorders on both carcinogenesis and the immune system. l-Arginine is essential for the maturation of the T cell receptor zeta (TCRζ), and its absence deprives T-cells of the ability to interact with tumor antigens. MDSCs deplete l-arginine due to a high expression of arginase 1 (ARG1) and their number increases 4-10 times depending on the type of the cancer. L-Arginine has been shown to be essential for the survival and progression of arginine auxotrophic tumors. However, the progression of arginine non-auxotrophic tumors is independent of exogenous l-arginine, because these tumors have arginine-succinate synthetase (ASS1) activity and are available to produce l-arginine from citrulline. Clinical studies have confirmed the high efficacy of arginine auxotrophic tumors therapy based on the elimination of l-arginine. However, l-arginine supplementation may improve the results of treatment of patients with arginine non-auxotrophic cancer. This review is an attempt to explain the seemingly contradictory results of oncological therapies based on the deprivation or supplementation of l-arginine.

Keywords: Auxotrophy; Cancer; Immune system; L-Arginine; Myeloid-derived suppressor cells.