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

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

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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.
Original languageEnglish
Article number12096
Pages (from-to)1-14
Number of pages14
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 14 Aug 2018

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Arginine
Urea
Argininosuccinate Synthase
Colorectal Neoplasms
oxaliplatin
Enzymes
Ornithine Carbamoyltransferase
Citrulline
Ornithine
Therapeutics
Fluorouracil
Arginase
Cell Line
Growth
Ammonia
Pharmaceutical Preparations
Neoplasms
Drug Therapy
ADI PEG20
Proteins

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Alexandrou, C., Al-Aqbi, S. S., Higgins, J. A., Boyle, W., Karmokar, A., Andreadi, C., ... Rufini, A. (2018). Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes. Scientific Reports, 8, 1-14. [12096]. https://doi.org/10.1038/s41598-018-30591-7

Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes. / Alexandrou, Constantinos; Al-Aqbi, Saif Sattar; Higgins, Jennifer A.; Boyle, William; Karmokar, Ankur; Andreadi, Catherine; Luo, Jin-Li; Moore, David A.; Viskaduraki, Maria; Blades, Matthew; Murray, Graeme I.; Howells, Lynne M.; Thomas, Anne; Brown, Karen; Cheng, Paul N.; Rufini, Alessandro.

In: Scientific Reports, Vol. 8, 12096, 14.08.2018, p. 1-14.

Research output: Contribution to journalArticle

Alexandrou, C, Al-Aqbi, SS, Higgins, JA, Boyle, W, Karmokar, A, Andreadi, C, Luo, J-L, Moore, DA, Viskaduraki, M, Blades, M, Murray, GI, Howells, LM, Thomas, A, Brown, K, Cheng, PN & Rufini, A 2018, 'Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes', Scientific Reports, vol. 8, 12096, pp. 1-14. https://doi.org/10.1038/s41598-018-30591-7
Alexandrou, Constantinos ; Al-Aqbi, Saif Sattar ; Higgins, Jennifer A. ; Boyle, William ; Karmokar, Ankur ; Andreadi, Catherine ; Luo, Jin-Li ; Moore, David A. ; Viskaduraki, Maria ; Blades, Matthew ; Murray, Graeme I. ; Howells, Lynne M. ; Thomas, Anne ; Brown, Karen ; Cheng, Paul N. ; Rufini, Alessandro. / Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes. In: Scientific Reports. 2018 ; Vol. 8. pp. 1-14.
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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.",
author = "Constantinos Alexandrou and Al-Aqbi, {Saif Sattar} and Higgins, {Jennifer A.} and William Boyle and Ankur Karmokar and Catherine Andreadi and Jin-Li Luo and Moore, {David A.} and Maria Viskaduraki and Matthew Blades and Murray, {Graeme I.} and Howells, {Lynne M.} and Anne Thomas and Karen Brown and Cheng, {Paul N.} and Alessandro Rufini",
note = "We thank Polaris Pharmaceuticals and Bio-Cancer Treatment for providing drugs and reagents. This work was supported by the Cancer Prevention Research Trust, with assistance from the Wellcome Trust Institutional Strategic Support Fund [097828/z/11/B], and Cancer Research UK in conjunction with the Department of Health as part of an Experimental Cancer Medicine Centre grant [C325/A15575]. C.A. was funded by a PhD fellowship from the Cancer Prevention Research Trust, S.S.A. was funded by a studentship from the Iraqi Government. We are thankful to John Bomalaski and Sara Galavotti for their critical reading of the manuscript and insightful suggestions. Finally, we are profoundly indebted to Professor Andreas Gescher for his constant support during the execution of this project and the writing of this manuscript.",
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N2 - 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.

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