Advertisement

Tumor Biology

, Volume 37, Issue 6, pp 7345–7355 | Cite as

Hyperoside induces apoptosis and inhibits growth in pancreatic cancer via Bcl-2 family and NF-κB signaling pathway both in vitro and in vivo

  • Yilong Li
  • Yongwei Wang
  • Le Li
  • Rui Kong
  • Shangha Pan
  • Liang Ji
  • Huan Liu
  • Hua ChenEmail author
  • Bei SunEmail author
Original Article

Abstract

Although advanced surgical operation and chemotherapy have been under taken, pancreatic cancer remains one of the most aggressive and fatal human malignancies with a low 5-year survival rate of less than 5 %. Therefore, novel therapeutic strategies for prevention and remedy are urgently needed in pancreatic cancer. This present research aimed to investigate the anti-cancer effects of hyperoside in human pancreatic cancer cells. Our in vitro results showed that hyperoside suppressed the proliferation and promoted apoptosis of two different human pancreatic cancer cell lines, which correlated with up-regulation of the ratios of Bax/Bcl-2 and Bcl-xL and down-regulation of levels of nuclear factor-κB (NF-κB) and NF-κB’s downstream gene products. What’s more, using an orthotopic model of human pancreatic cancer, we found that hyperoside also inhibited the tumor growth significantly. Mechanically, these outcomes could also be associated with the up-regulation of the ratios of Bax/Bcl-2 and Bcl-xL and down-regulation of levels of NF-κB and NF-κB’s downstream gene products. Collectively, our experiments indicate that hyperoside may be a promising candidate agent for the treatment of pancreatic cancer.

Keywords

Hyperoside Pancreatic cancer NF-κB Bcl-2 family 

Notes

Acknowledgments

This work was supported by the National Nature Scientific Foundation of China (No. 81372613, 81170431, 81302057), The National High Technology Research and Development Program of China (No. 2014AA020609), and Youth Science Foundation of Heilongjiang Province (No. QC2012C042).

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Bilimoria KY, Bentrem DJ, Ko CY, Ritchey J, Stewart AK, Winchester DP, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer. 2007;110(4):738–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Oettle H. Progress in the knowledge and treatment of advanced pancreatic cancer: from benchside to bedside. Cancer Treat Rev. 2014;40(9):1039–47.CrossRefPubMedGoogle Scholar
  3. 3.
    Ryan DP, Hong TS, Bardeesy H. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039–49.CrossRefPubMedGoogle Scholar
  4. 4.
    Hartwig W, Werner J, Jäger D, et al. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14(11):e476–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Li L, Aggarwal BB, Shishodia S, et al. Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer. 2004;101(10):2351–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Liptay S, Weber CK, Ludwig L, et al. Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer. Int J Cancer. 2003;105(6):735–46.CrossRefPubMedGoogle Scholar
  7. 7.
    Maier HJ, Schmidt-Strassburger U, Huber MA, et al. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295(2):214–28.CrossRefPubMedGoogle Scholar
  8. 8.
    Weichert W, Boehm M, Gekeler V, et al. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer. 2007;97(4):523–30.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Holcomb B, Yip-Schneider M, Schmidt CM. The role of nuclear factor kappaB in pancreatic cancer and the clinical applications of targeted therapy. Pancreas. 2008;36(3):225–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Diehl JA, Benzeno S. Cyclin D1 and pancreatic carcinoma: a proliferative agonist and chemotherapeutic antagonist. Clin Cancer Res. 2005;11(16):5665–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Greten FR, Weber CK, Greten TF, et al. Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology. 2002;123(6):2052–63.CrossRefPubMedGoogle Scholar
  12. 12.
    Zou Y, Lu Y, Wei D. Antioxidant activity of a flavonoid-rich extract of Hypericum perforatum L. in vitro. J Agric Food Chem. 2004;52(16):5032–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang WQ, Ma CG, Xu SY. Protective effect of hyperin against muocardial ischemia and reperfusion injury. Zhongguo Yao Li Xue Bao. 1997;17(4):341–4.Google Scholar
  14. 14.
    Zhou W, Oh J, Li W, et al. Phytochemical studies of Korean endangered plants: a new flavone from Rhododendron brachycarpum G. Don. Bull Kor Chem Soc. 2013;34(8):2535–38.CrossRefGoogle Scholar
  15. 15.
    Verma N, Amresh G, Sahu PK, et al. Pharmacological evaluation of hyperin for antihyperglycemic activity and effect on lipid profile in diabetic rats. Indian J Exp Biol. 2013;51(1):65–72.PubMedGoogle Scholar
  16. 16.
    Kim SJ, Um JY, Lee JY. Anti-inflammatory activity of hyperoside through the suppression of nuclear factor-κB activation in mouse peritoneal macrophages. Am J Chin Med. 2011;39(1):171–81.CrossRefPubMedGoogle Scholar
  17. 17.
    Rylski M, Duriasz-Rowińska H, Rewerski W. The analgesic action of some flavonoids in the hot plate test. Acta Physiol Pol. 1979;30(3):385–8.PubMedGoogle Scholar
  18. 18.
    Li FR, Yu FX, Yao ST, et al. Hyperin extracted from Manchurian rhododendron leaf induces apoptosis in human endometrial cancer cells through a mitochondrial pathway. Asian Pac J Cancer Prev. 2012;13(8):3653–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Yang FQ, Liu M, Li W, et al. Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA-21. Mol Med Rep. 2015;11(2):1085–92.PubMedGoogle Scholar
  20. 20.
    Zhang N, Ying MD, Wu YP, et al. Hyperoside, a flavonoid compound, inhibits proliferation and stimulates osteogenic differentiation of humanosteosarcoma cells. PLoS One. 2014;9(7):e98973.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang Y, Zhou Y, Jia G, Han B, Liu J, Teng Y, et al. Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: involvement of NF-κB signaling pathway. Biochem Pharmacol. 2014;88(3):322–33.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang Y, Zhou Y, Zhou H, Jia G, Liu J, et al. Pristimerin aauses G1 arrest, induces apoptosis, and enhances the chemosensitivity to gemcitabine in pancreatic cancer cells. PLoS ONE. 2012;7(8):e43826.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang YW, Wang SJ, Zhou YN, Pan SH, Sun B. Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo. J Cancer Res Clin Oncol. 2012;138(5):785–97.CrossRefPubMedGoogle Scholar
  24. 24.
    Metildi CA, Kaushal S, Luiken GA, Hoffman RM, Bouvet M. Advantages of fluorescence-guided laparoscopic surgery of pancreatic cancer labeled with fluorescent anti-carcinoembryonic antigen antibodies in an orthotopic mouse model. J Am Coll Surg. 2014;219:132–41.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Maawy AA, Hiroshima Y, Zhang Y, Heim R, Makings L, Garcia-Guzman M, et al. Near infrared photoimmunotherapy with anti-CEA-IR700 results in extensive tumor lysis and a significant decrease in tumor burden in orthotopic mouse models of pancreatic cancer. PLoS One. 2015;10:e0121989.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Maawy AA, Hiroshima Y, Zhang Y, Garcia-Guzman M, Luiken GA, Kobayashi H, et al. Photoimmunotherapy lowers recurrence after pancreatic cancer surgery in orthotopic nude mouse models. J Surg Res. 2015;197:5–11.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hiroshima Y, Maawy A, Hassanein MK, Menen R, Momiyama M, Murakami T, et al. The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid. PLoS One. 2014;9:e103382.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fu X, Guadagni F, Hoffman RM. A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci U S A. 1992;89:5645–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Furukawa T, Kubota T, Watanabe M, Kitajima M, Hoffman RM. A novel “patient-like” treatment model of human pancreatic cancer constructed using orthotopic transplantation of histologically intact human tumor tissue in nude mice. Cancer Res. 1993;53:3070–2.PubMedGoogle Scholar
  30. 30.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.CrossRefPubMedGoogle Scholar
  31. 31.
    Llambi F, Green DR. Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev. 2011;21(1):12–20.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122(Pt4):437–41.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27(50):6398–406.CrossRefPubMedGoogle Scholar
  34. 34.
    Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004;6(3):203–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen H, Sun B, Wang S, et al. Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-kappaB. J Cancer Res Clin Oncol. 2010;136(6):897–903.CrossRefPubMedGoogle Scholar
  37. 37.
    Kunnumakkara AB, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67(8):3853–61.CrossRefPubMedGoogle Scholar
  38. 38.
    Arora S, Bhardwaj A, Srivastava SK, et al. Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One. 2011;6(6):e21573.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Xiong HQ, Abbruzzese JL, Lin E, et al. NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer. 2004;108(2):181–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Pan X, Arumugam T, Yamamoto T, et al. Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008;14(24):8143–51.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sliva D. Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets. 2004;4(4):327–36.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

Personalised recommendations