Modifying role of apigenin in angiogenesis and anti-oxidant status in experimentally induced breast cancer in rats
Keywords:Angiogenesis, Thiobarbituric acid reactive substances, Apigenin, Anti-oxidant enzymes, 7, 12, dimethylbenzanthracene, Tamoxifen, Vascular endothelial growth factor
Background: Angiogenesis and agents which inhibit it are currently an alternative approach to anti-cancer therapy. Tumor metastasis and resistance to chemotherapy are factors to be considered in the management of breast cancer. Apigenin, a flavone is documented to possess anti-inflammatory, anti-oxidant, and anti-proliferative effects in vitro studies, but activity in vivo is still hypothetical.
Methods: Apigenin at doses of 50,100, 200 mg/kg body weight and tamoxifen at 50 mg/kg was administered to female albino Wistar rats and 7,12, dimethylbenzanthracene was used to induce mammary carcinogenesis. The anti-oxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were estimated in breast tissue and erythrocyte lysate with thiobarbituric acid reactive substances as an indicator of lipid peroxidation. Immunohistochemical staining for vascular endothelial growth factor (VEGF) protein expression was done to study its role in angiogenesis. The statistical significance of the data was determined using one-way analysis of variance and Dunnett’s multiple range test.
Results: Apigenin at doses of 100 mg/kg and 200 mg/kg (<0.05) was most effective in modifying the anti-oxidant status in breast tissue and in inhibiting VEGF expression in the immunohistochemical analysis in comparison with tamoxifen.
Conclusion: The results of our study implicate that apigenin, an innocuous agent could help alleviate the oxidative stress in breast cancer tissues, minimize toxicity of anti-cancer drugs and also slow down the process of angiogenesis in breast cancer.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55(1):10-30.
Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439(7074):353-7.
Barak V, Pe’er J, Kalickman I, Frenkel S. VEGF as a biomarker for metastatic uveal melanoma in humans. Curr Eye Res. 2011;36(4):386-90.
Caponigro F, Basile M, de Rosa V, Normanno N. New drugs in cancer therapy, National Tumor Institute, Naples, 17-18 June 2004. Anticancer Drugs. 2005;16(2):211-21.
Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001;90(2-3):157-77.
Meyer H, Bolarinwa A, Wolfram G, Linseisen J. Bioavailability of apigenin from apiin-rich parsley in humans. Ann Nutr Metab. 2006;50(3):167-72.
Chen H, Tritton TR, Kenny N, Absher M, Chiu JF. Tamoxifen induces TGF-beta 1 activity and apoptosis of human MCF-7 breast cancer cells in vitro. J Cell Biochem. 1996;61(1):9-17.
Moselhy SS, Al mslmani MA. Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzanthracene in sprague dawely female rats. Mol Cell Biochem. 2008;319(1-2):175-80.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8.
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys. 1984;21(2):130-2.
Sinha AK. Colorimetric assay of catalase. Anal Biochem. 1972;47:389-94.
Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179(4073):588-90.
Holmes K, Roberts OL, Thomas, AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(10):2003-12.
Liu LZ, Fang J, Zhou Q, Hu X, Shi X, Jiang BH. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. Mol Pharmacol. 2005;68(3):635-43.
Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein. FEBS Lett. 2004;575(1-3):59-63.
Yang CS, Landau JM, Huang MT, Newmark HL. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr. 2001;21:381-406.
Chen D, Landis-Piwowar KR, Chen MS, Dou QP. Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts. Breast Cancer Res. 2007;9(6):R80.
Yang SK, Dower WV. Metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomes. Proc Natl Acad Sci U S A. 1975;72(7):2601-5.
Lal H, Chugh K, Saini V, Kaur J, Saini AS. Effect of ageing on some free radical scavengers and the metabolic consequences in rats. Indian J Clin Biochem. 1992;7:143-6.
Choi EJ. Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci. 2008;82(21-22):1059-64.
Mates JM, Perez-Gomez C, Nunez de Castro I. Antioxidant enzymes and human diseases. Clin Biochem. 1999;32:595.
Kallio A, Zheng A, Dahllund J, Heiskanen KM, Härkönen P. Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells. Apoptosis. 2005;10(6):1395-410.
Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res. 2006;66(24):11954-66.
Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005;23(11):2469-76.
Long X, Fan M, Bigsby RM, Nephew KP. Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-α-dependent and -independent mechanisms. Mol Cancer Ther. 2008;2008;7(7):2096-108.
National Cancer Institute. Fact Sheet: targeted Cancer Therapies, 2012. Available at http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted#q1. Accessed 09 June 2014.