Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Abstract

Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming

“…To exploit this metabolic deficiency, multiple arginine destruction enzymes have been developed, including arginase, arginine decarboxylase, and arginine deiminase 1,11 . The most clinically relevant is PEGylated arginine deiminase (ADI-PEG20), which is currently in clinical trials 12 . ADI-PEG20 converts extracellular arginine to citrulline, which cannot be metabolized into arginine in the absence of ASS1 [13][14][15] .…”

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

“…For instance, LS-411N colon carcinoma cells, SU-DHL-5 B-cell lymphoma cells, and SNU-1 gastric carcinoma cells are sensitive to CAT1 deletion most likely because of low levels of ASS expression combined with low expression levels of y + LAT2 (SLC7A6). Arginine auxotrophy is frequently observed in melanoma, hepatocellular carcinoma, prostate cancer, and pancreatic cancer and can be exploited using arginine depletion [75]. Redundancy can be limited by concurrent targeting of GCN2, which showed significant synergy together with ASCT2ko [38] and asparaginase treatment [17,76].…”

Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms

“…Arginine is a semi-essential amino acid in humans, and its exogenous requirement is dependent on the stage of the organism’s development and its health status [ 2 , 3 ]. Arginine plays an important role in various molecular pathways regulating cell division, wound healing, neurological and immune functions, and hormone synthesis [ 1 , 4 , 5 ]. It is also a key precursor in the synthesis of cancer-associated compounds such as nitric oxide (NO) and polyamines [ 3 , 6 , 7 ].…”

“…In the normal condition, intracellular arginine homeostasis depends on dietary uptake, the degradation of intracellular proteins, efficiency of transport through cell membranes by cationic amino acid transporters (CATs), and de novo synthesis from aspartate and citrulline in the urea cycle [ 7 , 8 , 9 ]. There are two closely coupled enzymes, which are crucial in arginine biosynthesis: argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) [ 4 ]. The auxotrophy for arginine, in vivo, of several tumors, such as melanoma, hepatocellular carcinoma, some mesotheliomas, some renal cell cancers, and glioblastomas, is mainly related to the epigenetic silencing of ASS1 [ 9 , 10 , 11 ].…”

“…Arginine deprivation with recombinant arginine-degrading enzymes is considered as nontoxic and selective since it decreases viability and allows the control of the growth of malignant tumors that lack ASS1 expression [ 4 , 5 , 13 , 14 , 15 ]. Such a strategy is now under Phase I/II clinical trials for combating malignant melanomas, hepatocellular and pancreatic carcinomas, pleural mesotheliomas, thoracic cancers and other malignancies, and is well tolerated by the organism [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”