7,8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERα, PR, EGFR, and IGF1R: involvement of MAPK1/2-JNK1/2-Akt pathway
- 20 Downloads
Breast cancer (BC) is a persistent and impulsive metabolic disorder with the highest prevalence in women, worldwide. 7,12-Dimethylbenz(a)anthracene (DMBA) is a potent polyaromatic hydrocarbon (PAH)-based carcinogen producing mammary carcinomas in rats resembling the human hormone-dependent BC. 7,8-Dihydroxycoumarin (78DC) is a coumarin derivative that possesses diversified and favorable pharmacology profile to be considered in anticancer research against various malignancies. The present study was intended to investigate the antiproliferative and chemotherapeutic potentials of 78DC (20, 40, and 80 mg/kg BW) against DMBA (20 mg in olive oil)-induced mammary carcinoma Sprague-Dawley rats. We established the in silico approach for evaluation of the effect of 78DC on hormonal (estrogen receptor-α (ERα), progesterone receptor (PR)), growth factor receptors (EGFR and IGFR), 17β-hydroxysteroid dehydrogenase type 1 (17β-HD1), and aromatase. Effect of 78DC on estrogen synthesis, tumor growth, proliferation markers (Ki-67 and PCNA), cytokines (IL-10, IL-1β, IL-12), chemokine (MCP-1), and cellular expressions of ERα, PR, EGFR, IGF1R, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase was evaluated in mammary carcinoma bearing SD rats. DMBA induces large tumor burden and histological alterations in mammary gland with a subsequent increase in ERα, PR, EGFR, IGF1R, Ki-67, proliferating cell nuclear antigen (PCNA ), cytokines, and chemokine expressions. This was also correlated with the changes in rapid cell differentiation and proliferation. In contrast, 78DC treatment to the cancer-bearing animals abbreviated these changes and revealed to possess antitumorigenic and antiproliferative potentials. Further, a significant decrease in expressions of ERα, PR, EGFR, IGFR, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase signifies a reduction in estrogen sensitivity and secondary signaling pathways that may contribute to the prevention of tumor growth. The current findings revealed that 78DC potentially reduce cancer cell proliferation and reverted mammary cancer-induced changes in experimental animals in a dose-dependent manner.
KeywordsDMBA 7,8-Dihydroxycoumarin Proliferation markers ERα PR EGFR IGF1R Signaling pathway
Authors need to express thanks to University Grants Commission for the RGNF support (F1-17.1/2013-14/RGNF-2013-14-SC-CHH-46132). The authors are greatly acknowledging the authorities of the organizations of SP Pattanayak, A Kumar, and S Jha for the necessary infrastructure and facilities provided for the smooth running of the project.
Compliance with ethical standards
The study protocol was approved by IAEC (Institutional Animal Ethics Committee; Protocol Approval No. BIT/PH/IAEC/24/2013).
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Anbuselvam C, Vijayavel K, Balasubramanian MP (2007) Protective effect of Operculina turpethum against 7,12-dimethyl benz(a)anthracene induced oxidative stress with reference to breast cancer in experimental rats. Chem Biol Interact 168(3):229–236. https://doi.org/10.1016/j.cbi.2007.04.007 CrossRefPubMedGoogle Scholar
- 2.Arivazhagan L, Subramanian SP (2015) Tangeretin, a citrus flavonoid attenuates oxidative stress and protects hepatocellular architecture in rats with 7, 12-dimethylbenz (a) anthracene induced experimental mammary carcinoma. J Funct Foods 15:339–353. https://doi.org/10.1016/j.jff.2015.03.041 CrossRefGoogle Scholar
- 3.Benakanakere I, Besch-Williford C, Ellersieck MR, Hyder SM (2009) Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague-Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study. Endocr Relat Cancer 16(1):85–98. https://doi.org/10.1677/ERC-08-0069 CrossRefPubMedGoogle Scholar
- 8.Dickson R, Bano M, Johnson M, Shi Y, Martinez-Lacaci I, Amundadottir L et al (1994) Steroid regulation of growth factors and protooncogenes in the normal and malignant mammary gland, Protooncogenes and growth factors in steroid hormone induced growth and differentiation. CRC Press, Boca Raton, pp 143–174Google Scholar
- 14.Jimenez-Orozco FA, Rosales AA, Vega-Lopez A, Dominguez-Lopez ML, Garcia-Mondragon MJ, Maldonado-Espinoza A et al (2011) Differential effects of esculetin and daphnetin on in vitro cell proliferation and in vivo estrogenicity. Eur J Pharmacol 668(1–2):35–41. https://doi.org/10.1016/j.ejphar.2011.06.024 CrossRefPubMedGoogle Scholar
- 15.Kohama T, Terada S, Suzuki N, Inoue M (1997) Effects of dehydroepiandrosterone and other sex steroid hormones on mammary carcinogenesis by direct injection of 7, 12-dimethylbenz (a) anthracene (DMBA) in hyperprolactinemic female rats. Breast Cancer Res Treat 43(2):105–115. https://doi.org/10.1023/A:1005788326534 CrossRefPubMedGoogle Scholar
- 16.Kucinska M, Giron M-D, Piotrowska H, Lisiak N, Granig WH, Lopez-Jaramillo F-J, Salto R, Murias M, Erker T (2016) Novel promising estrogenic receptor modulators: cytotoxic and estrogenic activity of benzanilides and dithiobenzanilides. PLoS One 11(1):e0145615. https://doi.org/10.1371/journal.pone.0145615 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Kumar A, Jha S, Pattanayak SP (2015) Effect of naringenin on lipids, lipoproteins and lipid metabolising enzymes in 7,12-dimethyl benz(a)anthracene-induced mammary carcinogenesis in SD rats. Int J Pharm Pharm Sci 8(2)Google Scholar
- 20.Lu X, Hsieh T-C, Wu JM (2004) Equiguard™ suppresses androgen-dependent LNCaP prostate cancer cell proliferation by targeting cell cycle control via down regulation of the retinoblastoma protein Rb and induction of apoptosis via the release of cytochrome c. Int J Oncol 25(6):1801–1807PubMedGoogle Scholar
- 22.Mohamed MR, Emam MA, Hassan NS, Mogadem AI (2014) Umbelliferone and daphnetin ameliorate carbon tetrachloride-induced hepatotoxicity in rats via nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1 expression. Environ Toxicol Pharmacol 38(2):531–541. https://doi.org/10.1016/j.etap.2014.08.004 CrossRefPubMedGoogle Scholar
- 23.Pasqualini JR (2004) The selective estrogen enzyme modulators in breast cancer: a review. BBA-Rev Cancer 1654(2):123–143Google Scholar
- 24.Pattanayak SP, Sunita P, Mazumder PM (2014) Restorative effect of Dendrophthoe falcata (Lf) Ettingsh on lipids, lipoproteins, and lipid-metabolizing enzymes in DMBA-induced mammary gland carcinogenesis in Wistar female rats. Comp Clin Pathol 23(4):1013–1022. https://doi.org/10.1007/s00580-013-1736-2 CrossRefGoogle Scholar
- 27.Salhab M, Reed M, Al Sarakbi W, Jiang W, Mokbel K (2006) The role of aromatase and 17-Î2-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer. Breast Cancer Res Treat 99(2):155–162. https://doi.org/10.1007/s10549-006-9198-8 CrossRefPubMedGoogle Scholar
- 28.Sharma D, Smits BM, Eichelberg MR, Meilahn AL, Muelbl MJ, Haag JD et al (2011) Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One 6(10):e26145. https://doi.org/10.1371/journal.pone.0026145 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Shin S-J, Gong G, Lee HJ, Kang J, Bae YK, Lee A, Cho EY, Lee JS, Suh KS, Lee DW, Jung WH (2014) Positive expression of insulin-like growth factor-1 receptor is associated with a positive hormone receptor status and a favorable prognosis in breast cancer. J Breast Cancer 17(2):113–120. https://doi.org/10.4048/jbc.2014.17.2.113 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Shokoohinia Y, Hosseinzadeh L, Alipour M, Mostafaie A, Mohammadi-Motlagh H-R (2014) Comparative evaluation of cytotoxic and apoptogenic effects of several coumarins on human cancer cell lines: osthole induces apoptosis in p53-deficient H1299 cells. Adv Pharmacol Sci 2014:1–8. https://doi.org/10.1155/2014/847574 CrossRefGoogle Scholar
- 31.Song D, Liu G, Luu-The V, Zhao D, Wang L, Zhang H, Xueling G, Li S, Désy L, Labrie F, Pelletier G (2006) Expression of aromatase and 17β-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer: an immunocytochemical study. J Steroid Biochem Mol Biol 101(2):136–144. https://doi.org/10.1016/j.jsbmb.2006.06.015 CrossRefPubMedGoogle Scholar