Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy.

Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors.