The arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
    • Abstract:
      Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist in hosts and evade therapy. Accordingly, there is significant interest in drugging cancer-specific hypoxic responses. However, a major challenge in leukemia is identifying differential and druggable hypoxic responses between leukemic and normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of the urea cycle, is overexpressed in CML but not normal progenitors. ARG2 is a target of the hypoxia inducible factors (HIF1-α and HIF2-α), and is required for the generation of polyamines which are required for cell growth. We therefore explored if the clinically-tested arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) would be effective against leukemic cells under hypoxic conditions. Remarkably, nor-NOHA effectively induced apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Co-treatment with nor-NOHA overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. While nor-NOHA itself is promising in targeting the leukemia hypoxic response, we unexpectedly found that its anti-leukemic activity was independent of ARG2 inhibition. Genetic ablation of ARG2 using CRISPR/Cas9 had no effect on the viability of leukemic cells and their sensitivity towards nor-NOHA. This discrepancy was further evidenced by the distinct effects of ARG2 knockouts and nor-NOHA on cellular respiration. In conclusion, we show that nor-NOHA has significant but off-target anti-leukemic activity among ARG2-expressing hypoxic cells. Since nor-NOHA has been employed in clinical trials, and is widely used in studies on endothelial dysfunction, immunosuppression and metabolism, the diverse biological effects of nor-NOHA must be cautiously evaluated before attributing its activity to ARG inhibition.
      Competing Interests: The authors have declared that no competing interests exist.
    • References:
      Br J Pharmacol. 2009 Jul;157(6):922-30. (PMID: 19508396)
      J Clin Invest. 2010 Jul;120(7):2254-64. (PMID: 20592475)
      PLoS One. 2014 Jul 29;9(7):e103260. (PMID: 25072937)
      Mol Cell Biol. 2001 Feb;21(3):811-3. (PMID: 11154268)
      Cancer Res. 2015 Aug 1;75(15):3043-53. (PMID: 26054597)
      Am J Physiol Cell Physiol. 2010 Dec;299(6):C1541-8. (PMID: 20861464)
      Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15049-54. (PMID: 23980179)
      Cancer Res. 2001 Feb 1;61(3):1100-6. (PMID: 11221839)
      Nature. 2014 Sep 25;513(7519):559-63. (PMID: 25043024)
      Cancer Res. 2004 Aug 15;64(16):5839-49. (PMID: 15313928)
      Nat Immunol. 2016 Jun;17(6):656-65. (PMID: 27043409)
      Oncotarget. 2016 Jul 26;7(30):47221-47231. (PMID: 27363017)
      Cell. 2016 Oct 20;167(3):829-842.e13. (PMID: 27745970)
      Mol Cell Biol. 2002 Jul;22(13):4491-8. (PMID: 12052859)
      Eur J Drug Metab Pharmacokinet. 2017 Jun;42(3):355-370. (PMID: 27734327)
      Cell Stem Cell. 2013 Nov 7;13(5):549-63. (PMID: 24095676)
      Cell Stem Cell. 2011 Oct 4;9(4):298-310. (PMID: 21982230)
      Cardiovasc Res. 2013 Jun 1;98(3):334-43. (PMID: 23417041)
      Elife. 2017 Mar 24;6:. (PMID: 28337968)
      J Clin Endocrinol Metab. 2016 Nov;101(11):3952-3958. (PMID: 27399350)
      Clin Cancer Res. 2013 Dec 1;19(23):6506-19. (PMID: 24088735)
      PLoS One. 2012;7(7):e42038. (PMID: 22860052)
      Int J Cancer. 2008 Sep 1;123(5):1108-16. (PMID: 18528866)
      Int J Cell Cloning. 1983 Jun;1(2):105-17. (PMID: 6321612)
      Blood. 2014 Aug 14;124(7):1127-35. (PMID: 24994068)
      Exp Oncol. 2015 Jun;37(2):151-3. (PMID: 26112945)
      Cell. 2015 Jun 18;161(7):1553-65. (PMID: 26073944)
      Nat Methods. 2014 Aug;11(8):783-784. (PMID: 25075903)
      Trends Pharmacol Sci. 2015 Jun;36(6):374-83. (PMID: 25857287)
      J Intern Med. 2016 May;279(5):477-84. (PMID: 26707366)
      Nature. 2017 Jun 29;546(7660):662-666. (PMID: 28614294)
      Cancer Res. 2000 Jun 15;60(12):3305-12. (PMID: 10866325)
      Lab Invest. 2016 Aug;96(8):830-8. (PMID: 27239731)
      J Clin Oncol. 2011 Feb 10;29(5):591-9. (PMID: 21220598)
      Cell Stem Cell. 2011 Apr 8;8(4):399-411. (PMID: 21474104)
      Front Oncol. 2016 Feb 26;6:41. (PMID: 26955619)
      Nitric Oxide. 1999 Dec;3(6):427-38. (PMID: 10637120)
      Nat Med. 2015 Jun;21(6):591-600. (PMID: 25962123)
      Cell Stem Cell. 2010 Sep 3;7(3):391-402. (PMID: 20804974)
      Autophagy. 2014;10(12):2223-38. (PMID: 25484082)
      Nucleic Acids Res. 2003 Jul 1;31(13):3651-3. (PMID: 12824386)
      Blood. 2002 May 15;99(10):3792-800. (PMID: 11986238)
      J Hematol Oncol. 2008 Sep 25;1:14. (PMID: 18817562)
      Nat Rev Immunol. 2005 Aug;5(8):641-54. (PMID: 16056256)
      Hepatology. 2014 Apr;59(4):1366-80. (PMID: 23929677)
      Nat Rev Drug Discov. 2011 May;10(5):328-9. (PMID: 21532551)
      Nat Rev Drug Discov. 2011 Aug 31;10(9):712. (PMID: 21892149)
      Blood. 2013 Aug 1;122(5):749-58. (PMID: 23733335)
      Expert Opin Biol Ther. 2016;16(4):463-76. (PMID: 26679619)
      J Nutr. 2004 Oct;134(10 Suppl):2743S-2747S; discussion 2765S-2767S. (PMID: 15465778)
      J Clin Invest. 2003 Jul;112(1):126-35. (PMID: 12840067)
      Blood. 2012 Mar 15;119(11):2595-607. (PMID: 22275380)
      Blood. 2014 May 22;123(21):3316-26. (PMID: 24705490)
      Blood. 2002 Jan 1;99(1):394. (PMID: 11783438)
      Oncogene. 2017 Sep 21;36(38):5331-5340. (PMID: 28534514)
      Leukemia. 2010 Jul;24(7):1364-7. (PMID: 20508615)
      J Clin Invest. 2016 Jul 1;126(7):2465-81. (PMID: 27214549)
      Nat Rev Cancer. 2017 Jul;17(7):425-440. (PMID: 28524181)
      Blood. 2006 Sep 1;108(5):1627-34. (PMID: 16709924)
      Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17570-5. (PMID: 24101470)
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (N(omega)-hydroxynorarginine)
      0 (RNA, Small Interfering)
      94ZLA3W45F (Arginine)
      EC 3.5.3.1 (ARG2 protein, human)
      EC 3.5.3.1 (Arginase)
    • Publication Date:
      Date Created: 20181012 Date Completed: 20190320 Latest Revision: 20210405
    • Publication Date:
      20240104
    • Accession Number:
      PMC6181325
    • Accession Number:
      10.1371/journal.pone.0205254
    • Accession Number:
      30307989