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 (5FU), 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.

Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes / C. Alexandrou, S.S. Al-Aqbi, J.A. Higgins, W. Boyle, A. Karmokar, C. Andreadi, J. Luo, D.A. Moore, M. Viskaduraki, M. Blades, G.I. Murray, L.M. Howells, A. Thomas, K. Brown, P.N. Cheng, A. Rufini. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018 Aug 14), pp. 12096.1-12096.14. [10.1038/s41598-018-30591-7]

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

A. Rufini
Ultimo
2018

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 (5FU), 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.
Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Arginase; Arginine; Argininosuccinate Synthase; Cell Line, Tumor; Colon; Colorectal Neoplasms; Drug Interactions; Drug Synergism; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Humans; Hydrolases; Inhibitory Concentration 50; Kaplan-Meier Estimate; Male; Mice; Ornithine Carbamoyltransferase; Oxaliplatin; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Treatment Outcome; Urea; Xenograft Model Antitumor Assays
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/945774
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