Effects of curcumin on arginase enzyme activity, ornithine and nitric oxide levels in experimental breast cancer model

Year 2022, Volume: 39 Issue: 1, 36 - 40, 01.01.2022

Ezgi Kürkçü Kahraman , Nurettin Aydoğdu Hakan Erbaş

Abstract

Breast cancer accounts for almost 30% of all cancer types, making it the most common type of tumor among women in the world. Arginase, an essential enzyme of the urea cycle, leads to the formation of urea and ornithine from L-arginine using the same substrate as nitric oxide synthase (NOS). Arginase has been reported to be higher in cancer patients and can be used as a useful biomarker. In this study, we aimed to investigate the effects of curcumin, an anticarcinogenic agent, on arginase enzyme activity, ornithine, and nitric oxide (NO) levels in experimental breast cancer model in mice. 43 male Balb/c mice were used, and Erhlich acid tumor model was created in the study. Mice were divided into five groups as healthy control group, curcumin treatment before tumor formation, curcumin treatment after tumor formation and cancer control groups. 100 mg/kg curcumin were given orally. Serum and tissue arginase enzyme activities, NO levels and tissue ornithine levels were determined spectrophotometrically. Increased serum arginase activity decreased with curcumin treatment, but this difference was not statistically significant. On the other hand, decreased NO levels were increased with curcumin treatment. In tumor tissue, arginase activity and ornithine levels decreased significantly with curcumin treatment and tissue NO levels increased significantly with curcumin treatment. In our study, we show that curcumin may have a protective effect on the development of breast cancer by inhibiting arginase enzyme activity and ornithine levels, which are the precursors of polyamines, as well as inducing NO production via NOS. As a promising anticancer agent, the net effects of curcumin in this mechanism should be supported by more advanced studies and new parameters.

Keywords

arginase, breast cancer, curcumin, nitric oxide, ornithine

Project Number

794

References

• 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Vol. 61, CA: A Cancer Journal for Clinicians. 2011; 69–90.
• 2. Salimian Rizi B, Achreja A, Nagrath D. Nitric Oxide: The Forgotten Child of Tumor Metabolism. Vol. 3, Trends in Cancer. 2017.
• 3. Erbas H, Aydogdu N, Usta U, Erten O. Protective role of carnitine in breast cancer via decreasing arginase activity and increasing nitric oxide. Cell Biol Int. 2007;31(11).
• 4. Porembska Z, Luboiński G, Chrzanowska A, Mielczarek M, Magnuska J, Barańczyk-Kuźma A. Arginase in patients with breast cancer. Clin Chim Acta. 2003 Feb;328(1–2):105–11.
• 5. Singh R, Pervin S, Karimi A, Cederbaum S, Chaudhuri G. Activity in human breast cancer cell lines: N(ω)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res. 2000;60(12):3305–12.
• 6. Bansal V, Ochoa JB. Arginine availability, arginase, and the immune response. Vol. 6, Current Opinion in Clinical Nutrition and Metabolic Care. 2003; 223–8.
• 7. Efron DT, Barbul A. Arginine and nutrition in renal disease. Vol. 9, Journal of Renal Nutrition. 1999. p. 142–4.
• 8. Porembska Z, Skwarek A, Mielczarek M, Barańczyk-Kuźma A. Serum arginase activity in postsurgical monitoring of patients with colorectal carcinoma. Cancer. 2002 Jun 1;94(11):2930–4.
• 9. Leu S ‐Y, Wang S ‐R. Clinical significance of arginase in colorectal cancer. Cancer. 1992;70(4):733–6.
• 10. Štraus B, Čepelak I, Festa G. Arginase, a new marker of mammary carcinoma. Clin Chim Acta. 1992 Sep 15;210(1–2):5–12.
• 11. Erbaş H, Bal O, Çakır E. Effect of rosuvastatin on arginase enzyme activity and polyamine production in experimental breast cancer. Balkan Med J. 2015;32(1):89–95.
• 12. Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Vol. 6, Nature Reviews Cancer. 2006; 521–34.
• 13. Wang Y, Yu J, Cui R, Lin J, Ding X. Curcumin in Treating Breast Cancer: A Review. J Lab Autom. 2016;21(6):723–31.
• 14. Banik U, Parasuraman S, Adhikary AK, Othman NH. Curcumin: The spicy modulator of breast carcinogenesis. J Exp Clin Cancer Res. 2017;36(1):1–16.
• 15. Geyer JW, Dabich D. Rapid method for determination of arginase activity in tissue homogenates. Anal Biochem. 1971;39(2):412–7.
• 16. Photometric estimation of proline and ornithine. [Internet]. [cited 2020 Jun 22]. Available from: https://www.cabdirect.org/cabdirect/abstract/1953140123.
• 17. Lowry Oh, Rosebrough Nj, Farr Al, Randall Rj. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–75.
• 18. Munder M, Eichmann K, Morán JM, Centeno F, Soler G, Modolell M. Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol [Internet]. 1999;163(7):3771–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10490974
• 19. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Vol. 36, Clinical Chemistry. 1990. p. 1440–3.
• 20. Griffith OW, Stuehr DJ. Nitric Oxide Synthases: Properties and Catalytic Mechanism. Annu Rev Physiol [Internet]. 1995 Oct [cited 2020 Jun 22];57(1):707–34. Available from: https://pubmed.ncbi.nlm.nih.gov/7539994/
• 21. Hofseth LJ, Hussain SP, Wogan GN, Harris CC. Nitric oxide in cancer and chemoprevention. Vol. 34, Free Radical Biology and Medicine. 2003; 955–68.
• 22. Cui S, Reichner JS, Mateo RB, Albina JE. Activated Murine Macrophages Induce Apoptosis in Tumor Cells through Nitric Oxide-dependent or -independent Mechanisms. Cancer Res. 1994;54(9):2462–7.
• 23. Bonavida B, Khineche S, Huerta-Yepez S, Garbán H. Therapeutic potential of nitric oxide in cancer. Drug Resist Updat. 2006 Jun;9(3):157–73.
• 24. Caldwell RW, Rodriguez PC, Toque HA, Priya Narayanan S, Caldwell RB. Arginase: A multifaceted enzyme important in health and disease [Internet]. Vol. 98, Physiological Reviews. American Physiological Society; 2018 [cited 2020 Jun 22]; 641–65. Available from: https://pubmed.ncbi.nlm.nih.gov/29412048/
• 25. Lin JK, Lin-Shiau SY. Mechanisms of cancer chemoprevention by curcumin. Vol. 25, Proceedings of the National Science Council, Republic of China. Part B, Life sciences. 2001; 59–66.
• 26. Mokbel K, Mokbel K. Chemoprevention of Breast Cancer With Vitamins and Micronutrients: A Concise Review. In Vivo (Brooklyn). 2019;33(4):983–97.
• 27. Song X, Zhang M, Dai E, Luo Y. Molecular targets of curcumin in breast cancer (Review). Mol Med Rep. 2019;19(1):23–9.
• 28. Tan BL, Norhaizan ME. Curcumin combination chemotherapy: The implication and efficacy in cancer. Molecules. 2019;24(14):1–21.
• 29. Kumari M, Purohit MP, Pahuja R, Patnaik S, Shukla Y, Kumar P, et al. Pro-inflammatory macrophage polarization enhances the anti-cancer efficacy of self-assembled galactomannan nanoparticles entrapped with hydrazinocurcumin. Vol. 9, Drug Delivery and Translational Research. 2019; 1159–88.