Effect of Rosuvastatin on Arginase Enzyme Activity and Polyamine Production in Experimental Breast Cancer

Year 2015, Volume: 32 Issue: 1, 89 - 95, 01.01.2015

Hakan Erbaş Oğuz Bal Erol Çakır

Abstract

Background: Breast cancer is the most common malignant
tumour of women around the world. As a key
enzyme of the urea cycle, arginase leads to the formation
of urea and ornithine from L-arginine. In the patients
with several different cancers, arginase has been
found to be higher and reported to be a useful biological
marker.
Aims: The aim of this study was to investigate the effect
of rosuvastatin on serum and cancer tissue arginase
enzyme activity, and ornithine and polyamine (putrescine,
spermidine, spermine) levels.
Study Design: Animal experiment.
Methods: In this study, 50 male Balb/c mice were
used. Erchlich acid tumour cells were injected into the
subcutaneous part of their left foot. The mice were divided
into five groups: healthy control group, healthy
treatment, tumour control, treatment 1 and treatment 2.
Then, 1 mg/kg and 20 mg/kg doses of rosuvastatin
were given intraperitoneally. Serum and tissue arginase
enzyme activities and tissue ornithine levels were determined
spectrophotometrically. HPLC measurement
of polyamines were applied.
Results: Increased serum arginase activity and polyamine
levels were significantly decreased with rosuvastatin
treatment. In the tumour tissue, arginase activity
and ornithine levels were significantly decreased in
treatment groups compared to the tumour group. Tissue
polyamine levels also decreased with rosuvastatin
treatment.
Conclusion: We suggest that rosuvastatin may have
some protective effects on breast cancer development as
it inhibits arginase enzyme activity and ornithine levels,
precursors of polyamines, and also polyamine levels.
This protective effect may be through the induction of
nitric oxide (NO) production via nitric oxide synthase
(NOS). As a promising anticancer agent, the net effects
of rosuvastatin in this mechanism should be supported
with more advanced studies and new parameters.

Keywords

Arginase, breast cancer, ornithine, polyamines, rosuvastatin

References

• 1. Jenkinson CP, Grody WW, Caderbaum SD. Comparative properities of arginases. Comp Biochem Physiol B Biochem Mol Biol 1996;114:107-32. [CrossRef]
• 2. Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap? Mol Genet Metab 2004;81:S38-44. [CrossRef]
• 3. Porembska Z, Luboinski G, Chrzanowska A, Mielczarek M, Magnuska J, Baranczyk-Kuzma A. Arginase in patients with breast cancer. Clin Chim Acta 2003;328:105-11. [CrossRef]
• 4. Lowe DT. Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric Oxide 2000;4:441-58. [CrossRef]
• 5. Bonavida B, Khineche S, Huerta-Yepez S, Garban H. Therapeutic potential of nitric oxide in cancer. Drug Resist Updat 2006;9:157-73. [CrossRef]
• 6. Singh R, Avliyakulov NK, Braga M, Haykinson MJ, Martinez L, Singh V, et al. Proteomic identification of mitochondrial targets of arginase in human breast cancer. PLoS One 2013;8:115. [CrossRef]
• 7. Thomas T, Thomas TJ. Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci 2001;58:244-58. [CrossRef]
• 8. Wallace HM, Fraser AV, Hughes A. A perspective of polyamine metabolism. Biochem J 2003;376:1-14. [CrossRef]
• 9. Park MH, Igarashi K. Polyamines and their metabolites as diagnostic markers of human diseases. Biomol Ther (Seoul) 2013;21:1-9. [CrossRef]
• 10. Luvai A, Mbagaya W, Hall AS, Barth JH. Rosuvastatin: a review of the pharmacology and clinical effectiveness in cardiovascular disease. Clin Med Insights Cardiol 2012;6:17-33.
• 11. Kim YS, Ahn Y, Hong MH, Kim KH, Park HW, Hong YJ, et al. Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinase and Nuclear Factor-kappaB in endothelial cells. J Cardiovasc Pharmacol 2007;49:376-83. [CrossRef]
• 12. Schupp N, Schmid U, Heidland A, Stopper H. Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis. Atherosclerosis 2008;199:278-87. [CrossRef]
• 13. Kotamraju S, Williams CL, Kalyanaraman B. Statin-induced breast cancer cell death: role of inducible nitric oxide and arginase-dependent pathways. Cancer Res 2007;67:7386-94. [CrossRef]
• 14. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M. Th1/Th2- regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 1999;163:3771-7.
• 15. 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;31:1414-9. [CrossRef]
• 16. Fu S, Xiao C, Zhao W, Yu X. Polyamines analysis by HPLC and their application as tumor markers. Frontiers Biosci (Elite Ed.) 2012;4:1795-801.
• 17. Ishii N, Ikenaga H, Carmines PK,Aoki Y, Ogawa Z, Saruta T, et al. High glucose augments arginase activity and nitric oxide production in the renal cortex. Metabolism 2004;53:868-74. [CrossRef]