Advertisement

European Journal of Nutrition

, Volume 57, Issue 3, pp 981–989 | Cite as

Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms

  • Nahla E. El-Ashmawy
  • Naglaa F. Khedr
  • Hoda A. El-Bahrawy
  • Hend E. Abo Mansour
Original Contribution

Abstract

Purpose

The present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC.

Methods

SEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised.

Results

The anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group.

Conclusion

AMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.

Keywords

AMPK Cyclin D1 Doxorubicin Ginger Mammary carcinoma Solid Ehrlich carcinoma 

Notes

Acknowledgements

Authors gratefully acknowledge Dr. Mona A. Yehia, Professor of Histochemistry and Cell Biology, Medical Research Institute, Alexandria, for conducting and interpreting the histopathological examination.

References

  1. 1.
    Tan BS, Kang O, Mai CW, Tiong KH, Khoo AS, Pichika MR et al (2013) 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPAR γ). Cancer Lett 336(1):127–139CrossRefGoogle Scholar
  2. 2.
    Elbialy NS, Mady MM (2015) Ehrlich tumor inhibition using doxorubicin containing liposomes. Saudi Pharma J 23(2):182–187CrossRefGoogle Scholar
  3. 3.
    de Manincor M, Bensoussan A, Smith CA, Barr K, Schweickle M, Donoghoe LL et al (2016) Individualized yoga for reducing depression and anxiety, and improving well-being: a randomized controlled trial. Depress Anxiety. doi: 10.1002/da.22502 Google Scholar
  4. 4.
    Mielenz TJ, Xiao C, Callahan LF (2016) Self-management of arthritis symptoms by complementary and alternative medicine movement therapies. J Altern Complement Med 22(5):404–407CrossRefGoogle Scholar
  5. 5.
    Xie Y, Wan W, Zhao Y, Xie J, Wu Q (2016) Impacts on asthma at persistent stage and immune function in the patients treated with acupuncture for warming yang and benefiting qi. Zhongguo Zhen Jiu 35(11):1089–1093Google Scholar
  6. 6.
    Dişsiz G, Yilmaz M (2016) Complementary and alternative therapies and health literacy in cancer patients. Complement Ther Clin Pract 23:34–39CrossRefGoogle Scholar
  7. 7.
    Rajesh E, Sankari LS, Malathi L, Krupaa JR (2015) Naturally occurring products in cancer therapy. J Pharm Bioallied Sci. doi: 10.4103/0975-7406.155895 Google Scholar
  8. 8.
    Prasad S, Tyagi AK (2015) Ginger and its constituents: role in prevention and treatment of gastrointestinal cancer. Gastroenterol Res Pract. doi: 10.1155/2015/142979 Google Scholar
  9. 9.
    Höferl M, Stoilova I, Wanner J, Schmidt E, Jirovetz L, Trifonova D et al (2015) Composition and comprehensive antioxidant activity of ginger (Zingiber officinale) essential oil from Ecuador. Nat Prod Commun 10(6):1085–1090Google Scholar
  10. 10.
    Mangprayool T, Kupittayanant S, Chudapongse N (2013) Participation of citral in the bronchodilatory effect of ginger oil and possible mechanism of action. Fitoterapia 89:68–73CrossRefGoogle Scholar
  11. 11.
    Anfenan ML (2014) Evaluation of nutritional and anti-diabetic activity of different forms of ginger in rats. Middle East J Sci Res 21(1):56–62.Google Scholar
  12. 12.
    Hessien M, Doniaa T, El-Gendy S, Abou Sikkenaa M (2013) Unfractionated green tea and ginger polyphenols induce apoptotic, cytotoxic and antioxidant effects in hepatoma cells. J Herbal Med 3:87–98CrossRefGoogle Scholar
  13. 13.
    Liu Y, Whelan RJ, Pattnaik BR, Ludwig K, Subudhi E, Rowland H, et al (2012) Terpenoids from Zingiber officinale (Ginger) induce apoptosis in endometrial cancer cells through the activation of p53. Plos One. doi: 10.1371/journal.pone.0053178 Google Scholar
  14. 14.
    Park GH, Park JH, Song HM, Eo HJ, Kim MK, Lee JW et al (2014) Anti-cancer activity of ginger (Zingiber officinale) leaf through the expression of activating transcription factor 3 in human colorectal cancer cells. BMC Complement Altern Med 14(1):408CrossRefGoogle Scholar
  15. 15.
    Plengsuriyakarn T, Viyanant V, Eursitthichai V, Tesana S, Chaijaroenkul W, Itharat A et al (2012) Cytotoxicity, toxicity, and anticancer activity of Zingiber officinale Roscoe against cholangiocarcinoma. Asia Pac J Cancer Prev 9:4597–4606Google Scholar
  16. 16.
    Jeena K, Liju VB, Kuttan R (2013) Antioxidant, anti-inflammatory and anti-nociceptive activities of essential oil from ginger. Indian J Physiol Pharmacol 57(1):51–62Google Scholar
  17. 17.
    Tsuboi K, Matsuo Y, Shamoto T et al (2014) Zerumbone inhibits tumor angiogenesis via NF-κB in gastric cancer. Oncol Rep 31(1):57–64CrossRefGoogle Scholar
  18. 18.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11(8):558–572CrossRefGoogle Scholar
  19. 19.
    Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262CrossRefGoogle Scholar
  20. 20.
    Shahabuddin MS, Nambiar M, Moorthy BT, Naik PL, Choudhary B (2011) A novel structural derivative of natural alkaloid ellipticine, MDPSQ, induces necrosis in leukemic cells. Invest New Drugs 29:523–533CrossRefGoogle Scholar
  21. 21.
    Habib SH, Makpol S, Abdul Hamid NA, Das S, Ngah WZ, Yusof YA (2008) Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics 63(6):807–813CrossRefGoogle Scholar
  22. 22.
    Iliopoulos D, Hirsch HA, Struhl K (2011) Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 71(9): 3196–201.CrossRefGoogle Scholar
  23. 23.
    Cosetti M, Yu GP, Schantz SP (2008) Five-year survival rates and time trends of laryngeal cancer in the US population. Arch Otolaryngol Head Neck Surg 134(4):370–379CrossRefGoogle Scholar
  24. 24.
    Osman Ael-M, Ahmed MM, Khayyal MT, el-Merzabani MM (1993) Hyperthermic potentiation of ciplatin cytotoxicity on solid Ehrlich carcinoma. Tumori 79(4):268–272Google Scholar
  25. 25.
    Salem ML, Shoukry NM, Teleb WK, Abdel-Daim MM, Abdel-Rahman MA (2016) In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model. SpringerPlus. doi: 10.1186/s40064-016-2269-3 Google Scholar
  26. 26.
    Glasel J (1995) Validity of nucleic acid purities monitored by 260 nm/280 nm absorbance ratios. Biotechniques 18(1):62–63Google Scholar
  27. 27.
    Gu Y, Zhang S, Wu Q, Xu S, Cui Y, Yang Z et al (2010) Differential expression of decorin, EGFR and cyclin D1 during mammary gland carcinogenesis. JECCR. doi: 10.1186/1756-9966-29-6 Google Scholar
  28. 28.
    Field A (2009) Discovering statistics using SPSS. Sage, LondonGoogle Scholar
  29. 29.
    Anampa J, Makower D, Sparano JA (2015) Progress in adjuvant chemotherapy for breast cancer: an overview. BMC Med. doi: 10.1186/s12916-015-0439-8 Google Scholar
  30. 30.
    Bukhari SN, Jantan I, Seyed MA (2015) Effects of plants and isolates of Celastraceae family on cancer pathways. Anticancer Agents Med Chem 15(6):681–693CrossRefGoogle Scholar
  31. 31.
    Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25(3):304–317CrossRefGoogle Scholar
  32. 32.
    Khedr NF, Khalil RM (2015) Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin. Tumour Biol 36(12):9267–9275CrossRefGoogle Scholar
  33. 33.
    Wang S, Song P, Zou M (2012) Inhibition of AMP-activated protein kinase α (AMPK α) by doxorubicin accentuates genotoxic stress and cell death in mouse embryonic fibroblasts and cardiomyocytes. J Biol Chem 287(11):8001–8012CrossRefGoogle Scholar
  34. 34.
    Gratia S, Kay L, Potenza L, Seffouh A, Novel-Chate V, Schnebelen C et al (2012) Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress. Cardiovasc Res 95(3):290–299CrossRefGoogle Scholar
  35. 35.
    Roufogalis BD (2014) Zingiber officinale (ginger): a future outlook on its potentiain prevention and treatment of diabetes and prediabetic state. New J Sci. doi: 10.1155/2014/674684.Google Scholar
  36. 36.
    Carling D, Mayer FV, Sanders MJ, Gamblin SJ (2011) AMP activated protein kinase: nature’s energy sensor. Nat Chem Biol 7:512–518CrossRefGoogle Scholar
  37. 37.
    Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y et al (2015) Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol 212(4):479.e1-479.e10CrossRefGoogle Scholar
  38. 38.
    Wu D, Wu P, Zhao L, Huang L, Zhang Z, Zhao S et al (2015) NF-κB expression and outcomes in solid tumors: a systematic review and meta-analysis. Medicine (Baltimore). doi: 10.1097/MD.0000000000001687 Google Scholar
  39. 39.
    Napetschnig J, Wu H (2013) Molecular basis of NF-κB signaling. Annu Rev Biophys 42:19.1–19.26CrossRefGoogle Scholar
  40. 40.
    Esparza Lopez J, Medina-Franco H, Escobar-Arriaga E, Leon-Rodrı´guez E, Zentella-Dehesa A, Ibarra-Sa´nchez MJ (2013) Doxorubicin induces atypical NF-jB activation through c-Abl kinase activity in breast cancer cells. J Cancer Res Clin Oncol 139:1625–1635CrossRefGoogle Scholar
  41. 41.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar
  42. 42.
    Abdullah S, Zainal Abidin SA, Murad NA, Makpol S, Wan Ngah WZ, Yusof YA (2010) Ginger extract (Zingiber officinale) triggers apoptosis and G0/G1 cells arrest in HCT 116 and HT 29 colon cancer cell lines. Afr J Biochem Res 4(4):134–42Google Scholar
  43. 43.
    Wee LH, Morad NA, Aan GJ, Makpol S, Ngah WZ, Yusof YA (2015) Mechanism of chemoprevention against colon cancer cells using combined Gelam honey and Ginger extract via mTOR and Wnt/β-catenin pathways. Asia Pac J Cancer Prev 16(15): 6549–56CrossRefGoogle Scholar
  44. 44.
    Saha A, Blando J, Silver E, Beltran L (2014) 6-Shogaol from dried ginger inhibits growth of prostate cancer cells both in vitro and in vivo through inhibition of STAT3 and NF-kB signaling. Cancer Prev Res 7:627–638CrossRefGoogle Scholar
  45. 45.
    Rezaei PF, Fouladdel S, Ghaffari SM, Amin G, Azizi E (2012) Induction of G1 cell cycle arrest and cyclin D1 down-regulation in response to pericarp extract of Baneh in human breast cancer T47D cells. J Pharm Sci. doi: 10.1186/2008-2231-20-101 Google Scholar
  46. 46.
    Huang KZ, Nie DN, Yin SM, Li YQ, Xie SF, Ma LP et al (2011) Cyclin D1, hTERT expression and telomerase activity in HL-60 and HL-60A cell lines and their significance. J Exp Hematol 19(4):911–915Google Scholar
  47. 47.
    Żuryń A, Litwiniec A, Klimaszewska-Wiśniewska A, Nowak JM, Gackowska L, Myśliwiec BJ, Pawlik A, Grzanka A (2014) Expression of cyclin D1 after treatment with doxorubicin in the HL-60 cell line. Cell Biol Int 38(7):857–867CrossRefGoogle Scholar
  48. 48.
    Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endoc M 298(4):E751–E760Google Scholar
  49. 49.
    Narala SR, Allsopp RC, Wells TB, Zhang G, Prasad P, Coussens MJ, Rossi DJ, Weissman IL, Vaziri H (2008) SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. Mol Biol Cell 19(3):1210–9CrossRefGoogle Scholar
  50. 50.
    Mohanty S, Mohanty A, Sandoval N, Tran T, Bedell V, Wu J et al (2016) Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines. Leukemia Lymphoma 23:1–3Google Scholar
  51. 51.
    Brahmbhatt M, Gundala SR, Asif G, Shamsi SA, Aneja R (2013) Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation. Nutr Cancer 65(2):263–272CrossRefGoogle Scholar
  52. 52.
    Thorna CF, Oshiroa C, Marshe S, Hernandez-Boussardb T, McLeodd H, Teri Kleina TE et al (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genom 21(7):440–446CrossRefGoogle Scholar
  53. 53.
    Tacar O, Sriamornsak P, Dass CR (2013) Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 65(2):157–170CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Nahla E. El-Ashmawy
    • 1
  • Naglaa F. Khedr
    • 1
  • Hoda A. El-Bahrawy
    • 1
  • Hend E. Abo Mansour
    • 1
  1. 1.Department of Biochemistry, Faculty of PharmacyTanta UniversityTantaEgypt

Personalised recommendations