Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes
Articolo
Data di Pubblicazione:
2018
Citazione:
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]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
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
Elenco autori:
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
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