Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition
Patrycja Marzęta-Assas, Damian Jacenik, Zbigniew Zasłona
Abstract
Arginases are key enzymes that hydrolyze L-arginine to urea and L-ornithine in the urea cycle. The two arginase isoforms, arginase 1 (ARG1) and arginase 2 (ARG2), regulate the proliferation of cancer cells, migration, and apoptosis; affect immunosuppression; and promote the synthesis of polyamines, leading to the development of cancer. Arginases also compete with nitric oxide synthase (NOS) for L-arginine, and their participation has also been confirmed in cardiovascular diseases, stroke, and inflammation. Due to the fact that arginases play a crucial role in the development of various types of diseases, finding an appropriate candidate to inhibit the activity of these enzymes would be beneficial for the therapy of many human diseases. In this review, based on numerous experimental, preclinical, and clinical studies, we provide a comprehensive overview of the biological and physiological functions of ARG1 and ARG2, their molecular mechanisms of action, and affected metabolic pathways. We summarize the recent clinical trials' advances in targeting arginases and describe potential future drugs.