Skip to main content

Advertisement

SpringerLink
Log in

Oxymatrine induces apoptosis and inhibits invasion in Gallbladder carcinoma via PTEN/PI3K/AKT pathway

  • Original Article
  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

Oxymatrine extracted from Sophora flavescens Ait as a natural polyphenolic phytochemical has been demonstrated to exhibit anti-tumor effects on various cancers, including Gallbladder carcinoma (GBC). However, its underlying mechanisms of function are largely unknown in GBC cells. The present study is conducted to investigate the anti-tumor effects and the underlying mechanisms of oxymatrine on GBC cells in vitro and in vivo. The results showed that oxymatrine inhibited cell viability, metastatic ability and induced cell apoptosis in dose-dependent manners. Furthermore, we found that the expression of p-AKT, MMP-2, MMP-9 and the ratio of Bcl-2/Bax were significantly down-regulated, while the expression of PTEN was up-regulated in GBC cells. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly antagonized the oxymatrine-mediated inhibition of GBC–SD cells. Subsequently, our in vivo studies showed that administration of oxymatrine induced a significant dose-dependent decrease in tumor growth. In conclusion, these findings indicated that the inhibition of cells proliferation, migration, invasion and the induction of apoptosis in response to oxymatrine in GBC cells, may function through the suppression of PTEN/PI3K/AKT pathway, which was considered as the vital signaling pathway in regulating tumorigenesis. These results suggested that oxymatrine might be a novel effective candidate as chemotherapeutic agent against GBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abahssain H, Afchain P, Meals N, Ismaili N, Rahali R, Rabit HM, Errihani H (2010) Chemotherapy in gallbladder carcinoma. Presse Med 39:1238–1245

    Article  Google Scholar 

  • And DJN, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    Article  Google Scholar 

  • Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout GB, Bahar I (2006) Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores. Biophys J 90:1546–1559

    Article  CAS  Google Scholar 

  • Boutros C, Gary M, Baldwin K, Somasundar P (2012) Gallbladder cancer: past, present and an uncertain future. Surg Oncol 21:183–191

    Article  Google Scholar 

  • Butler MS (2008) ChemInform abstract: natural products to drugs: natural product derived compounds in clinical trials. Cheminform 39:162–195

    Google Scholar 

  • Cao YG, Jing S, Li L, Gao JQ, Shen ZY, Liu Y, Xing Y, Wu ML, Wang Y, Xu CQ, Sun HL (2010) Antiarrhythmic effects and ionic mechanisms of oxymatrine from Sophora flavescens. Phytother Res 24:1844–1849

    Article  CAS  Google Scholar 

  • Chai NL, Fu Q, Shi H, Cai CH, Wan J, Xu SP, Wu BY (2012) Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells. World J Gastroenterol 18:4199–4206

    Article  CAS  Google Scholar 

  • Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270

    Article  CAS  Google Scholar 

  • Chen H, Zhang J, Luo J, Lai F, Wang Z, Tong H, Lu D, Bu H, Zhang R, Lin S (2013a) Antiangiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF-kappaB-mediated VEGF signaling pathway. Oncol Rep 30:589–595

    Article  CAS  Google Scholar 

  • Chen JS, Huang X, Wang Q, Huang JQ, Zhang L, Chen XL, Lei J, Cheng ZX (2013b) Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. Carcinogenesis 34:10–19

    Article  CAS  Google Scholar 

  • Dai ZJ, Gao J, Wu WY, Wang XJ, Li ZF, Kang HF, Liu XX, Ma XB (2007) Effect of matrine injections on invasion and metastasis of gastric carcinoma SGC-7901 cells in vitro. Zhong Yao Cai 30:815–819

    CAS  Google Scholar 

  • Gan YH, Zhang S (2009) PTEN/AKT pathway involved in histone deacetylases inhibitor induced cell growth inhibition and apoptosis of oral squamous cell carcinoma cells. Oral Oncol 45:e150–e154

    Article  CAS  Google Scholar 

  • Garcia-Echeverria C, Sellers W (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511–5526

    Article  CAS  Google Scholar 

  • Gu XB, Yang XJ, Hua Z, Lu ZH, Zhang B, Zhu YF, Wu HY, Jiang YM, Chen HK, Pei H (2012) Effect of oxymatrine on specific cytotoxic T lymphocyte surface programmed death receptor-1 expression in patients with chronic hepatitis B. Chin Med J 125:1434–1438

    CAS  Google Scholar 

  • Guo B, Zhang T, Su J, Wang K, Lin X (2015) Oxymatrine targets EGFR p-Tyr845, and inhibits EGFR-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. Cancer Chemother Pharmacol 75:353–363

    Article  CAS  Google Scholar 

  • Hale AJ, Smith CA, Sutherland LC (1996) Apoptosis: molecular regulation of cell death. Eur J Biochem 236:1–26

    Article  CAS  Google Scholar 

  • Ho JW, Hon PN, Chim WO (2009) Effects of oxymatrine from Ku Shen on cancer cells. Anticancer Agents Med Chem 9:823–826

    Article  CAS  Google Scholar 

  • Jia J, Li S, Gong W, Ding J, Fang C, Quan Z (2011) Mda-7/IL-24 induces apoptosis in human GBC–SD gallbladder carcinoma cells via mitochondrial apoptotic pathway. Oncol Rep 25:195–201

    CAS  Google Scholar 

  • Jin UH, Suh SJ, Chang HW, Son JK, Lee SH, Son KH, Chang YC, Kim CH (2008) Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. J Cell Biochem 104:15–26

    Article  CAS  Google Scholar 

  • Khan SA, Toledano MB, Taylor-Robinson SD (2008) Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB 10:77–82

    Article  CAS  Google Scholar 

  • Lao Y (2005) Clinical study on effect of matrine injection to protect the liver function for patients with primary hepatic carcinoma after trans-artery chemo-embolization (TAE). Zhong Yao Cai 28:637–638

    Google Scholar 

  • Li M, Shen J, Wu X, Zhang B, Zhang R, Weng H, Ding Q, Tan Z, Gao G, Mu J, Yang J, Shu Y, Bao R, Ding Q, Wu W, Cao Y, Liu Y (2013) Downregulated expression of hepatoma-derived growth factor (HDGF) reduces gallbladder cancer cell proliferation and invasion. Med Oncol 30:1–8

    Google Scholar 

  • Li J, Jiang K, Zhao F (2015) Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA-29b and downregulating matrix metalloproteinase-2 expression. Mol Med Rep 12:145–151

    Google Scholar 

  • Liu F, He Y, Liang Y, Wen L, Zhu Y, Wu Y, Zhao LX, Li YS, Mao XL, Liu HY (2013a) PI3-kinase inhibition synergistically promoted the anti-tumor effect of lupeol in hepatocellular carcinoma. Cancer Cell Int 13:1223–1227

    CAS  Google Scholar 

  • Liu TY, Tan ZJ, Jiang L, Gu JF, Wu XS, Cao Y, Li ML, Wu KJ, Liu YB (2013b) Curcumin induces apoptosis in gallbladder carcinoma cell line GBC–SD cells. Cancer Cell Int 13:1–9

    Article  CAS  Google Scholar 

  • Liu Y, Xu Y, Ji WD (2014) Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol 3:5111–5119

    Article  Google Scholar 

  • Miller G, Jarnagin WR (2008) Gallbladder carcinoma. Eur J Surg Oncol 34:306–312

    Article  CAS  Google Scholar 

  • Orrenius S (2006) Mitochondrial regulation of apoptotic cell death. Toxicol Lett 149:19–23

    Article  Google Scholar 

  • Pan L, Chai H, Kinghorn AD (2010) The continuing search for antitumor agents from higher plants. Phytochem Lett 3:1–8

    Article  CAS  Google Scholar 

  • Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279–296

    Article  CAS  Google Scholar 

  • Qin X, Yin J, Zhang H (2009) Effects of oxymatrine on proliferation of HepG2 cells. China J Chin Mater Med 34:1426–1429

    CAS  Google Scholar 

  • Shao Q (2011) The recent effect of radiotherapy combined with compound kushen injection for esophageal cancer. Radiother Oncol 99:S372–S373

    Article  Google Scholar 

  • Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, Raina V, Shukla NK, Thulkar S, Garg P, Chaudhary SP (2010) Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 28:4581–4586

    Article  CAS  Google Scholar 

  • Shima I, Sasaguri Y, Kusukawa J, Yamana H, Fujita H, Kakegawa T, Morimatsu M (1992) Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of esophageal carcinoma. A Clinicopathologic study. Cancer 70:2747–2753

    Article  CAS  Google Scholar 

  • Song MQ, Zhu JS, Chen JL, Wang L, Da W, Li Zhu, Zhang WP (2007) Synergistic effect of oxymatrine and angiogenesis inhibitor NM-3 on modulating apoptosis in human gastric cancer cells. World J Gastroenterol 13:1788–1793

    Article  CAS  Google Scholar 

  • Sun M, Cao H, Sun L, Dong S, Bian Y, Han J, Zhang L, Ren S, Hu Y, Liu C, Xu L, Liu P (2012a) Antitumor activities of kushen: literature review. Evid Based Complement Alternat Med 2012:373219

    Google Scholar 

  • Sun Q, Ma W, Gao Y, Zheng W, Zhang B, Peng Y (2012b) Meta-analysis: therapeutic effect of transcatheter arterial chemoembolization combined with compound kushen injection in hepatocellular carcinoma. Afr J Tradit Complement Altern Med 9:178–188

    Google Scholar 

  • Tan Z, Zhang S, Li M, Wu X, Weng H, Ding Q, Cao Y, Bao R, Shu Y, Mu J, Ding Q, Wu W, Yang J, Zhang L, Liu Y (2013) Regulation of cell proliferation and migration in gallbladder cancer by zinc finger X-chromosomal protein. Gene 528:261–266

    Article  CAS  Google Scholar 

  • Tanioka Y, Yoshida T, Yagawa T, Saiki Y, Takeo S, Harada T, Okazawa T, Yanai H, Okita K (2004) Matrix metalloproteinase-7 and Matrix metalloproteinase-9 are associated with unfavourable prognosis in superfical oesophageal cancer. Br J Cancer 89:2116–2121

    Article  Google Scholar 

  • Valeriote F, Corbett T, Lorusso P, Moore RE, Scheuer P, Patterson G (2015) Anticancer agents from natural products. Pharm Biol 33:59–66

    Article  Google Scholar 

  • Wang YP, Zhao W, Xue R, Zhou ZX, Liu F, Han YX, Ren G, Peng ZG, Cen S, Chen HS, Li YH, Jiang JD (2011a) Oxymatrine inhibits hepatitis B infection with an advantage of overcoming drug-resistance. Antivir Res 89:227–231

    Article  CAS  Google Scholar 

  • Wang S, Yu S, Shi W, Ge L, Yu X, Fan J, Zhang J (2011b) Curcumin inhibits the migration and invasion of mouse hepatoma Hca-F cells through down-regulating caveolin-1 expression and epidermal growth factor receptor signaling. IUBMB Life 63:775–782

    Article  CAS  Google Scholar 

  • Xie M, Yi X, Wang RJ, Zhu M, Qi C, Liu Y, Ye Y, Tan S, Tang A (2014) 14-thienyl methylene matrine (YYJ18), the derivative from matrine, induces apoptosis of human nasopharyngeal carcinoma cells by targeting MAPK and PI3K/Akt pathways in vitro. Cell Physiol Biochem 33:1475–1483

    Article  CAS  Google Scholar 

  • Yang L, Yang L, Tian WC, Li J, Liu J, Zhu M, Zhang Y, Yang Y, Liu F, Zhang Q, Liu Q, Shen Y, Qi Z (2014) Resveratrol plays dual roles in pancreatic cancer cells. J Cancer Res Clin Oncol 140:749–755

    Article  CAS  Google Scholar 

  • Yun SJ, Kim WJ (2013) Role of the epithelial–mesenchymal transition in bladder cancer: from prognosis to therapeutic target. Korean J Urol 54:645–650

    Article  Google Scholar 

  • Zhang Y, Zhang H, Yu P, Liu Q, Liu K, Duan HY, Luan GL, Yagasaki K, Zhang GY (2009) Effects of matrine against the growth of human lung cancer and hepatoma cells as well as lung cancer cell migration. Cytotechnology 59:191–200

    Article  CAS  Google Scholar 

  • Zhang S, Zhang Y, Zhuang Y, Wang J, Ye J, Zhang S, Wu JB, Yu K, Han YX (2012) Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation. PLoS ONE 7:e46853

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Program for integrative medicine of Suzhou City (No. SYSD2015163).

Author information

Author notes

    Authors and Affiliations

    1. Department of General Surgery, Wujiang No.1 People’s Hospital, Suzhou, 215200, China

      Liqiang Qian, Penghui Ye, Gang Wang, Wei Dai, Yan Liu, Quangen Gao & Genhai Shen

    2. Department of Gynaecology and Obstetrics, Health Center of Songling, Suzhou, 215200, China

      Xiaqin Li

    Authors
    1. Liqiang Qian
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiaqin Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Penghui Ye
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Gang Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Wei Dai
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yan Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Quangen Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Genhai Shen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Quangen Gao or Genhai Shen.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Liqiang Qian and Xiaqin Li contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Qian, L., Li, X., Ye, P. et al. Oxymatrine induces apoptosis and inhibits invasion in Gallbladder carcinoma via PTEN/PI3K/AKT pathway. Cytotechnology 70, 83–94 (2018). https://doi.org/10.1007/s10616-017-0153-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10616-017-0153-9

    Keywords

    Search

    Navigation