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Journal of Environmental Pathology, Toxicology and Oncology
IF: 1.625 5-Year IF: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN Print: 0731-8898
ISSN Online: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvironPatholToxicolOncol.2019031445
pages 13-21

Nobiletin Attenuates Cell Proliferation by Modulating the Activating Protein-1 Signaling Pathway in 7,12-Dimethylbenz[a]anthracene-Induced Mammary Carcinogenesis

Huazhi Zhang
Department of Medical Oncology, Affiliated Jinan Third Hospital of Jining Medical University, Jinan, Shandong Province, 250132, China
Ping Lv
Department of Hematology, The Fourth People's Hospital of Jinan City, Jinan, Shandong Province, 250031, China
Zhanzhan Xiao
Department of Emergency Services, The Fourth People's Hospital of Jinan City, Jinan, Shandong Province, 250031, China
Elamaran Ananda Jothi
CAS in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai, India 608502
Jiangfei Yang
Department of Medical Imaging, Shandong Provincial Hospital Affiliated with Shandong University, Huaiyin District, Jinan, Shandong 250021, People's Republic of China


Breast cancer is a widespread disease that affects women globally. Diagnostic processes and remedial approaches to breast carcinogenesis have improved in recent decades, but continuous survival of patients with breast carcinogenesis is still lacking due to increased cell proliferation. The aim of the present work is to explore the anticell proliferative effects of nobiletin (NOB) against 7,12-dimethylbenz[a]anthracene (DMBA)-treated mammary tumorigenesis in rats. We stimulate mammary carcinogenesis using oral gavage of DMBA (25 mg/kg body weight) mixed with olive oil (1 mL). This results in reduced body weight; increased liver marker enzymes such as alkaline phosphatase, acid phosphatase, aspartate aminotransferase, and alanine aminotransferase; and cell proliferative markers such as c-Jun, proliferating cell nuclear antigen, c-Fos, cyclin D1, and activating protein-1 (AP-1) in the DMBA-treated cancer-bearing animals. NOB administration improved body weight, significantly reduced hepatic marker enzymes, and altered histopathological changes. Furthermore, NOB efficiently reduced tumor cell proliferation markers in DMBA-induced mammary carcinogenesis. Overall, these results suggest that NOB has an anticell proliferative effect on DMBA-induced mammary cancer via modulation of the AP-1 signaling pathway.


  1. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: convergence of incidence rates between black and white women. Cancer J Clin. 2016 Jan;66(1):31-42.

  2. Weinstein IB. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis. 2000 May 1;21(5):857-64.

  3. Jitariu AA, Cimpean AM, Ribatti D, Raica M. Triple negative breast cancer: the kiss of death. Oncotarget. 2017 Jul 11;8(28):46652.

  4. Zhang P, Zhou H, Lu K, Lu Y, Wang Y, Feng T. Exo-some-mediated delivery of MALAT1 induces cell proliferation in breast cancer. OncoTargets Ther. 2018;11:291.

  5. Karin M. Nuclear factor-KB in cancer development and progression. Nature. 2006 May;441(7092):431.

  6. Lu C, Shen Q, DuPre E, Kim H, Hilsenbeck S, Brown PH. cFos is critical for MCF-7 breast cancer cell growth. Oncogene. 2005 Sep;24(43):6516.

  7. Schiff R, Reddy P, Ahotupa M, Coronado-Heinsohn E, Grim M, Hilsenbeck SG, Lawrence R, Deneke S, Herrera R, Chamness GC, Fuqua SA. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst. 2000 Dec 6;92(23):1926-34.

  8. Farombi EO, Shrotriya S, Surh YJ. Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-KB and AP-1. Life Sci. 2009 Jan 30;84(5-6):149-55.

  9. Bishayee A, Ahmed S, Brankov N, Perloff M. Triter-penoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci. 2011 Jan 1;16:980.

  10. Sinha D, Biswas J, Sung B, Aggarwal B, Bishayee A. Chemopreventive and chemotherapeutic potential of curcumin in breast cancer. Curr Drug Targets. 2012 Dec 1;13(14):1799-819.

  11. Li W, Wang X, Niu X, Zhang H, He Z, Wang Y, Zhi W, Liu F. Protective effects of nobiletin against endotoxic shock in mice through inhibiting TNF-a, IL-6, and HMGB1 and regulating NF-KB pathway. Inflammation. 2016 Apr 1;39(2):786-97.

  12. Lee YC, Cheng TH, Lee JS, Chen JH, Liao YC, Fong Y, Wu CH, Shih YW. Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/ Akt and small GTPase signals in human gastric adeno-carcinoma AGS cells. Mol Cellular Biochem. 2011 Jan 1;347(1-2):103-15.

  13. Ihara H, Yamamoto H, Ida T, Tsutsuki H, Sakamoto T, Fujita T, Okada T, Kozaki S. Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of citrus unshiu in rat primary astrocytes. Biosci Biotechnol Biochem. 2012;76(10):1843-8.

  14. Miyata Y, Tanaka H, Shimada A, Sato T, Ito A, Yamanouchi T, Kosano H. Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxy-flavonoids, nobiletin and tangeretin. Life Sci. 2011 Mar 28;88(13-14):613-8.

  15. Zhang L, Zhang X, Zhang C, Bai X, Zhang J, Zhao X, Chen L, Wang L, Zhu C, Cui L, Chen R. Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo. Brain Res. 2016 Apr 1;1636:130-41.

  16. Yoshigai E, Machida T, Okuyama T, Mori M, Murase H, Yamanishi R, Okumura T, Ikeya Y, Nishino H, Nishizawa M. Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1P-treated hepatocytes. Biochem Biophys Res Commun. 2013 Sep 13;439(1):54-9.

  17. Tominari T, Hirata M, Matsumoto C, Inada M, Miyaura C. Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis. J Pharmacol Sci. 2012;119(4):390-4.

  18. Parkar NA, Bhatt LK, Addepalli V. Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardio-vascular dysfunction of diabetes in rats. Food Funct. 2016;7(7):3121-9.

  19. Chen C, Ono M, Takeshima M, Nakano S. Antiproliferative and apoptosis-inducing activity of nobiletin against three subtypes of human breast cancer cell lines. Anticancer Res. 2014 Apr 1;34(4):1785-92.

  20. Bergmeyer HU, Scheibe P, Wahlefeld AW. Optimization of methods for aspartate aminotransferase and alanine aminotransferase. Clin Chem. 1978 Jan 1;24(1): 58-73.

  21. Anbuselvam C, Vijayavel K, Balasubramanian MP. Protective effect of Operculina turpethum against 7,12-dimethylbenz(a)anthracene induced oxidative stress with reference to breast cancer in experimental rats. Chem Biol Interact. 2007 Jul 20;168(3):229-36.

  22. Arivazhagan L, Pillai SS. Tangeretin, a citrus pentame-thoxyflavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(a) anthracene-induced rat mammary carcinoma. J Nutr Biochem. 2014 Nov 1;25(11):1140-53.

  23. Bava SV, Puliyappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-KB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2005 Feb 25;280(8):6301-8.

  24. Moselhy SS. Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzan-thracene in Sprague Dawley female rats. Mol Cell Biochem. 2008 Dec 1;319(1-2):175-80.

  25. Bishayee A, Mandal A, Thoppil RJ, Darvesh AS, Bhatia D. Chemopreventive effect of a novel oleanane triterpenoid in a chemically induced rodent model of breast cancer. Int J Cancer. 2013 Sep 1;133(5):1054-63.

  26. Wang Z, Zhang X. Chemopreventive activity of honokiol against 7,12-dimethylbenz[a]anthracene-induced mammary cancer in female Sprague Dawley rats. Front Pharmacol. 2017 May 31;8:320.

  27. Contreras-Zentella ML, Hernandez-Munoz R. Is liver enzyme release really associated with cell necrosis induced by oxidant stress? Oxid Med Cell Longev. 2016;2016 :3529149.

  28. Padmavathi R, Senthilnathan P, Sakthisekaran D. Thera-peutic effect of propolis and paclitaxel on hepatic phase I and II enzymes and marker enzymes in dimethyl-benz(a)anthracene-induced breast cancer in female rats. Comp Biochem Physiol C Toxicol Pharmacol. 2006 Jul 1;143(3):349-54.

  29. Shaulian E, Karin M. AP-1 As a regulator of cell life and death. Nat Cell Biol. 2002 May;4(5):E131.

  30. Malkas LH, Herbert BS, Abdel-Aziz W, Dobrolecki LE, Liu Y, Agarwal B, Hoelz D, Badve S, Schnaper L, Arnold RJ, Mechref Y. A cancer-associated PCNA expressed in breast cancer has implications as a potential biomarker. Proc Natl Acad Sci. 2006 Dec 19;103(51):19472-7.

  31. Fu J, Cheng L, Wang Y, Yuan P, Xu X, Ding L, Zhang H, Jiang K, Song H, Chen Z, Ye Q. The RNA-binding protein RBPMS1 represses AP-1 signaling and regulates breast cancer cell proliferation and migration. Biochim Biophys Acta Mol Cell Res. 2015 Jan 1;1853(1):1-3.

  32. Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer. 2005 Nov 1;41(16):2449-61.

  33. Caldon CE, Sutherland RL, Musgrove EA. Cell cycle proteins in epithelial cell differentiation: Implications for breast cancer. Cell Cycle. 2010 May 15;9(10): 1918-28.

  34. Liu J, Wang S, Tian S, He Y, Lou H, Yang Z, Kong Y, Cao X. Nobiletin inhibits breast cancer via p38 mitogen-activated protein kinase, nuclear transcription factor-KB, and nuclear factor erythroid 2-related factor 2 pathways in MCF-7 cells. Food Nutr Res. 2018 Nov 21;62. doi: 10.29219/fnr.v62.1323.

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