Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
October-2018 Volume 40 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
October-2018 Volume 40 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models

  • Authors:
    • Sze‑Kwan Lam
    • Kin Pong U
    • Yuan‑Yuan Li
    • Shi Xu
    • Paul Ning‑Man Cheng
    • James Chung‑Man Ho
  • View Affiliations / Copyright

    Affiliations: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China, Bio‑Cancer Treatment International, Hong Kong, SAR, P.R. China, Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China, Bio‑Cancer Treatment International, Hong Kong, SAR, P.R. China
    Copyright: © Lam et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1994-2004
    |
    Published online on: July 25, 2018
       https://doi.org/10.3892/or.2018.6598
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Arginine depletion has shown anticancer effects among arginine auxotrophic cancers. An anti‑proliferative effect of pegylated arginase (BCT‑100) has been shown in acute myeloid leukaemia, hepatocellular carcinoma and mesothelioma. The aim of the present study was to evaluate the effect of BCT‑100 in lung adenocarcinoma. A panel of lung adenocarcinoma cell lines and xenograft models were used to investigate the effect of BCT‑100. Protein expression, arginine level, putrescine level, spermidine level and apoptosis were analyzed by western blotting, ELISA, high performance liquid chromatography, dot blot and TUNEL assay, respectively. BCT‑100 converts arginine to ornithine. BCT‑100 reduced in vitro cell viability across different lung adenocarcinoma cell lines and suppressed tumour growth in an HCC4006 xenograft, while paradoxical growth stimulation was observed in H358, HCC827, H1650 and H1975 xenografts. Upon BCT‑100 treatment, ornithine decarboxylase 1 (ODC1) was induced in two solid tumour xenografts (H1650 and H1975). It was postulated that the accumulated ornithine could be channeled via ODC1 to produce polyamines that promoted tumour growth. The action of an ODC1 inhibitor (α‑difluoromethylornithine, DFMO) was studied in the restoration of the anticancer effects of BCT‑100 in lung adenocarcinoma. In both H1650 and H1975 xenografts, a combination of DFMO and BCT‑100 significantly suppressed tumour growth, resulting in doubled median survival compared with the control. Putrescine was decreased in almost all treatment arms in the H1650, H1975 and HCC4006 xenografts. Nonetheless spermidine was reduced only following DFMO/BCT‑100 treatment in the H1650 and H1975 xenografts. Apoptosis was enhanced in the combined treatment arm in both H1650 and H1975 xenografts. In the HCC4006 xenograft, addition of DFMO did not alter the tumour suppressive effect of BCT‑100. In conclusion, inhibition of ODC1 by DFMO was crucial in facilitating BCT‑100 treatment in lung adenocarcinoma that was partially mediated by depleting arginine and polyamines with consequent apoptosis.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T and Szlosarek PW: Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 126:2762–2772. 2010.PubMed/NCBI

2 

Chow AK, Ng L, Li Sing H, Cheng CW, Lam CS, Yau TC, Cheng PN, Fan ST, Poon RT and Pang RW: Anti-tumor efficacy of a recombinant human arginase in human hepatocellular carcinoma. Curr Cancer Drug Targets. 12:1233–1243. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Feun L and Savaraj N: Pegylated arginine deiminase: A novel anticancer enzyme agent. Exp Opin Invest Drugs. 15:815–822. 2006. View Article : Google Scholar

4 

Thomas T and Thomas TJ: Polyamines in cell growth and cell death: Molecular mechanisms and therapeutic applications. Cell Mol Life Sci. 58:244–258. 2001. View Article : Google Scholar : PubMed/NCBI

5 

Tanios R, Bekdash A, Kassab E, Stone E, Georgiou G, Frankel AE and Abi-Habib RJ: Human recombinant arginase I(Co)-PEG5000 [HuArgI(Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human acute myeloid leukemia cells. Leuk Res. 37:1565–1571. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Cheng PN, Lam TL, Lam WM, Tsui SM, Cheng AW, Lo WH and Leung YC: Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res. 67:309–317. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Lam SK, Li YY, Xu S, Leung LL; U KP, ; Zheng YF, Cheng PN and Ho JC: Growth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts. Respir Res. 18:802017. View Article : Google Scholar : PubMed/NCBI

8 

Lam TL, Wong GK, Chow HY, Chong HC, Chow TL, Kwok SY, Cheng PN, Wheatley DN, Lo WH and Leung YC: Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis. Pigment Cell Melanoma Res. 24:366–376. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Lam TL, Wong GK, Chong HC, Cheng PN, Choi SC, Chow TL, Kwok SY, Poon RT, Wheatley DN, Lo WH, et al: Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest. Cancer Lett. 277:91–100. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Yau T, Cheng PN, Chan P, Chen L, Yuen J, Pang R, Fan ST, Wheatley DN and Poon RT: Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma. Invest New Drugs. 33:496–504. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Lam SK, Li YY, Zheng CY and Ho JC: Downregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma. Int J Oncol. 46:113–122. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Li YY, Lam SK, Mak JC, Zheng CY and Ho JC: Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer. Lung Cancer. 81:354–361. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Brenner T, Fleming TH, Spranz D, Schemmer P, Bruckner T, Uhle F, Martin EO, Weigand MA and Hofer S: Reactive metabolites and AGE-RAGE-mediated inflammation in patients following liver transplantation. Mediators Inflamm. 2013:5014302013. View Article : Google Scholar : PubMed/NCBI

14 

Nicoletti R, Venza I, Ceci G, Visalli M, Teti D and Reibaldi A: Vitreous polyamines spermidine, putrescine, and spermine in human proliferative disorders of the retina. Br J Ophthalmol. 87:1038–1042. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Ho JC, Tam TC and Lam SK: Salvage therapy beyond targeted therapy in lung adenocarcinoma. Semin Respir Crit Care Med. 34:837–844. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Qiu F, Huang J and Sui M: Targeting arginine metabolism pathway to treat arginine-dependent cancers. Cancer Lett. 364:1–7. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Mussai F, Egan S, Higginbotham-Jones J, Perry T, Beggs A, Odintsova E, Loke J, Pratt G; U KP, ; Lo A, et al: Arginine dependence of acute myeloid leukemia blast proliferation: A novel therapeutic target. Blood. 125:2386–2396. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Majumdar R, Shao L, Minocha R, Long S and Minocha SC: Ornithine: The overlooked molecule in the regulation of polyamine metabolism. Plant Cell Physiol. 54:990–1004. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Shantz LM and Levin VA: Regulation of ornithine decarboxylase during oncogenic transformation: Mechanisms and therapeutic potential. Amino Acids. 33:213–223. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Svensson KJ, Welch JE, Kucharzewska P, Bengtson P, Bjurberg M, Påhlman S, Dam Ten GB, Persson L and Belting M: Hypoxia-mediated induction of the polyamine system provides opportunities for tumor growth inhibition by combined targeting of vascular endothelial growth factor and ornithine decarboxylase. Cancer Res. 68:9291–9301. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Miller-Fleming L, Olin-Sandoval V, Campbell K and Ralser M: Remaining mysteries of molecular biology: The role of polyamines in the cell. J Mol Biol. 427:3389–3406. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Russell DH and Snyder SH: Amine synthesis in regenerating rat liver: Extremely rapid turnover of ornithine decarboxylase. Mol Pharmacol. 5:253–262. 1969.PubMed/NCBI

23 

Meyskens FL Jr, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, Kelloff G, Lawson MJ, Kidao J, McCracken J, et al: Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: A randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila). 1:32–38. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Mackenzie GG, Ouyang N, Xie G, Vrankova K, Huang L, Sun Y, Komninou D, Kopelovich L and Rigas B: Phospho-sulindac (OXT-328) combined with difluoromethylornithine prevents colon cancer in mice. Cancer Prev Res. 4:1052–1060. 2011. View Article : Google Scholar

25 

Chen Y, Hu J, Boorman D, Klein-Szanto A and O'Brien TG: Therapy of murine squamous cell carcinomas with 2-difluoromethylornithine. J Carcinog. 3:102004. View Article : Google Scholar : PubMed/NCBI

26 

Schipper RG, Penning LC and Verhofstad AA: Involvement of polyamines in apoptosis. Facts and controversies: Effectors or protectors? Semin Cancer Biol. 10:55–68. 2000. View Article : Google Scholar : PubMed/NCBI

27 

Tomasi ML, Ryoo M, Skay A, Tomasi I, Giordano P, Mato JM and Lu SC: Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer. Exp Cell Res. 319:1902–1911. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Rounbehler RJ, Li W, Hall MA, Yang C, Fallahi M and Cleveland JL: Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res. 69:547–553. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Wang MF, Liao YF, Hung YC, Lin CL, Hour TC, Lue KH, Hung HC and Liu GY: Hydroxydibenzoylmethane induces apoptosis through repressing ornithine decarboxylase in human promyelocytic leukemia HL-60 cells. Exp Mol Med. 43:189–196. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Fung MKL and Chan GC: Drug-induced amino acid deprivation as strategy for cancer therapy. J Hematol Oncol. 10:1442017. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Lam SK, U KP, Li YY, Xu S, Cheng PN and Ho JC: Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncol Rep 40: 1994-2004, 2018.
APA
Lam, S., U, K.P., Li, Y., Xu, S., Cheng, P.N., & Ho, J.C. (2018). Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncology Reports, 40, 1994-2004. https://doi.org/10.3892/or.2018.6598
MLA
Lam, S., U, K. P., Li, Y., Xu, S., Cheng, P. N., Ho, J. C."Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models". Oncology Reports 40.4 (2018): 1994-2004.
Chicago
Lam, S., U, K. P., Li, Y., Xu, S., Cheng, P. N., Ho, J. C."Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models". Oncology Reports 40, no. 4 (2018): 1994-2004. https://doi.org/10.3892/or.2018.6598
Copy and paste a formatted citation
x
Spandidos Publications style
Lam SK, U KP, Li YY, Xu S, Cheng PN and Ho JC: Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncol Rep 40: 1994-2004, 2018.
APA
Lam, S., U, K.P., Li, Y., Xu, S., Cheng, P.N., & Ho, J.C. (2018). Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncology Reports, 40, 1994-2004. https://doi.org/10.3892/or.2018.6598
MLA
Lam, S., U, K. P., Li, Y., Xu, S., Cheng, P. N., Ho, J. C."Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models". Oncology Reports 40.4 (2018): 1994-2004.
Chicago
Lam, S., U, K. P., Li, Y., Xu, S., Cheng, P. N., Ho, J. C."Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models". Oncology Reports 40, no. 4 (2018): 1994-2004. https://doi.org/10.3892/or.2018.6598
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team