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.Peer reviewedPublisher PD

Al-Aqbi, Saif Sattar

Alexandrou, Constantinos

Andreadi, Catherine

Blades, Matthew

Boyle, William

Brown, Karen

Cheng, Paul N.

Higgins, Jennifer A.

Howells, Lynne M.

Karmokar, Ankur

Luo, Jin-Li

Moore, David A.

Murray, Graeme I.

Rufini, Alessandro

Thomas, Anne

Viskaduraki, Maria

Scientific Reports

English

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

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

UCL Discovery

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

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

C Alexandrou (7812554)

SS Al-Aqbi (7755575)

JA Higgins (7812557)

W Boyle (7812560)

A Karmokar (7750502)

C Andreadi (7747625)

J-L Luo (7812563)

DA Moore (7752410)

M Viskaduraki (7748243)

M Blades (7782473)

GI Murray (7812566)

LM Howells (7755581)

A Thomas (841916)

K Brown (7679720)

PN Cheng (7812569)

A Rufini (7642934)

Leicester Research Archive

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

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.Peer reviewe

Aberdeen University Research

https://aura.abdn.ac.uk/bitstream/2164/10897/1/s41598_018_30591_7.pdf

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

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UCL Discovery

Leicester Research Archive

Aberdeen University Research