Human arginase I: a potential broad-spectrum anti-cancer agent

Abstract

With high rates of morbidity and mortality, cancer continues to pose a serious threat to public health on a global scale. Considering the discrepancies in metabolism between cancer and normal cells, metabolism-based anti-cancer biopharmaceuticals are gaining importance. Normal cells can synthesize arginine, but they can also take up extracellular arginine, making it a semi-essential amino acid. Arginine auxotrophy occurs when a cancer cell has abnormalities in the enzymes involved in arginine metabolism and relies primarily on extracellular arginine to support its biological functions. Taking advantage of arginine auxotrophy in cancer cells, arginine deprivation, which can be induced by introducing recombinant human arginase I (rhArg I), is being developed as a broad-spectrum anti-cancer therapy. This has led to the development of various rhArg I variants, which have shown remarkable anti-cancer activity. This article discusses the importance of arginine auxotrophy in cancer and different arginine-hydrolyzing enzymes that are in various stages of clinical development and reviews the need for a novel rhArg I that mitigates the limitations of the existing therapies. Further, we have also analyzed the necessity as well as the significance of using rhArg I to treat various arginine-auxotrophic cancers while considering the importance of their genetic profiles, particularly urea cycle enzymes.

Keywords: Arginase I; Auxotrophy; Cancer; Fusion technology; PEGylation.

Fig. 1

The expression of ASS1 and OTC in normal cells ensures a steady supply of arginine through the catalysis of citrulline and ornithine, respectively. However, the loss of ASS1 and OTC expression causes arginine metabolism to be dysfunctional in arginine-auxotrophic cancer. ADI-PEG 20 and rhArg I deplete extracellular arginine to citrulline and ornithine, respectively, which cause the apoptosis and autophagy of the cancer cells (the figure was created using free medical images available from Servier Medical Art at: smart.servier.com)

Fig. 2

Arginine-auxotrophic cancer statistics, 2020 (the figure was created using Prism—GraphPad software)

Fig. 3

Adverse effects of different treatments of cancer (the figure was created using free medical images available from Servier Medical Art at: smart.servier.com)