Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes.

Abstract	Tumors deficient in the urea cycle enzymes argininosuccinate synthase-1 (ASS1) and ornithine transcarbamylase (OTC) are unable to synthesize arginine and can be targeted using arginine-deprivation therapy. Here, we show that colorectal cancers (CRCs) display negligible expression of OTC and, in subset of cases, ASS1 proteins. CRC cells fail to grow in arginine-free medium and dietary arginine deprivation slows growth of cancer cells implanted into immunocompromised mice. Moreover, we report that clinically-formulated arginine-degrading enzymes are effective anticancer drugs in CRC. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine to citrulline and ammonia, affects growth of ASS1-negative cells, whereas recombinant human arginase-1 (rhArg1peg5000), which degrades arginine into urea and ornithine, is effective against a broad spectrum of OTC-negative CRC cell lines. This reflects the inability of CRC cells to recycle citrulline and ornithine into the urea cycle. Finally, we show that arginase antagonizes chemotherapeutic drugs oxaliplatin and 5-fluorouracil (5-FU), whereas ADI-PEG20 synergizes with oxaliplatin in ASS1-negative cell lines and appears to interact with 5-fluorouracil independently of ASS1 status. Overall, we conclude that CRC is amenable to arginine-deprivation therapy, but we warrant caution when combining arginine deprivation with standard chemotherapy.
Authors	Constantinos Alexandrou, Saif Sattar Al-Aqbi, Jennifer A Higgins, William Boyle, Ankur Karmokar, Catherine Andreadi, Jin-Li Luo, David A Moore, Maria Viskaduraki, Matthew Blades, Graeme I Murray, Lynne M Howells, Anne Thomas, Karen Brown, Paul N Cheng, Alessandro Rufini
Journal	Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 12096 (08 14 2018) ISSN: 2045-2322 [Electronic] England
PMID	30108309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Recombinant Proteins Oxaliplatin Polyethylene Glycols Urea Arginine Ornithine Carbamoyltransferase Hydrolases ARG1 protein, human Arginase ADI PEG20 Argininosuccinate Synthase Fluorouracil
Topics	Aged Animals Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use) Arginase (pharmacology, therapeutic use) Arginine (antagonists & inhibitors, metabolism) Argininosuccinate Synthase (metabolism) Cell Line, Tumor Colon (pathology) Colorectal Neoplasms (drug therapy, mortality, pathology) Drug Interactions Drug Synergism Feasibility Studies Female Fluorouracil (pharmacology, therapeutic use) Follow-Up Studies Humans Hydrolases (pharmacology, therapeutic use) Inhibitory Concentration 50 Kaplan-Meier Estimate Male Mice Ornithine Carbamoyltransferase (metabolism) Oxaliplatin (pharmacology, therapeutic use) Polyethylene Glycols (pharmacology, therapeutic use) Recombinant Proteins (pharmacology, therapeutic use) Retrospective Studies Treatment Outcome Urea (metabolism) Xenograft Model Antitumor Assays

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