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Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies
Author(s) -
Christin Riess,
Fatemeh Shokraie,
Carl Friedrich Classen,
Bernd Kreikemeyer,
Tomas Fiedler,
Christian Junghanß,
Claudia Maletzki
Publication year - 2018
Publication title -
cellular physiology and biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.486
H-Index - 87
eISSN - 1421-9778
pISSN - 1015-8987
DOI - 10.1159/000495382
Subject(s) - arginine deiminase , arginine , argininosuccinate synthase , cancer research , cancer , protein arginine methyltransferase 5 , biology , medicine , pharmacology , biochemistry , methylation , methyltransferase , citrulline , gene , amino acid
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.

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