, Volume 70, Issue 1, pp 83–94 | Cite as

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

  • Liqiang Qian
  • Xiaqin Li
  • Penghui Ye
  • Gang Wang
  • Wei Dai
  • Yan Liu
  • Quangen GaoEmail author
  • Genhai ShenEmail author
Original Article


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.


Oxymatrine Gallbladder carcinoma Invasion PTEN AKT 



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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abahssain H, Afchain P, Meals N, Ismaili N, Rahali R, Rabit HM, Errihani H (2010) Chemotherapy in gallbladder carcinoma. Presse Med 39:1238–1245CrossRefGoogle Scholar
  2. And DJN, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477CrossRefGoogle Scholar
  3. 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 90:1546–1559CrossRefGoogle Scholar
  4. Boutros C, Gary M, Baldwin K, Somasundar P (2012) Gallbladder cancer: past, present and an uncertain future. Surg Oncol 21:183–191CrossRefGoogle Scholar
  5. Butler MS (2008) ChemInform abstract: natural products to drugs: natural product derived compounds in clinical trials. Cheminform 39:162–195Google Scholar
  6. 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 24:1844–1849CrossRefGoogle Scholar
  7. 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 18:4199–4206CrossRefGoogle Scholar
  8. Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270CrossRefGoogle Scholar
  9. 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 30:589–595CrossRefGoogle Scholar
  10. 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 34:10–19CrossRefGoogle Scholar
  11. 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 30:815–819Google Scholar
  12. 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–e154CrossRefGoogle Scholar
  13. Garcia-Echeverria C, Sellers W (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511–5526CrossRefGoogle Scholar
  14. 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 125:1434–1438Google Scholar
  15. 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 75:353–363CrossRefGoogle Scholar
  16. Hale AJ, Smith CA, Sutherland LC (1996) Apoptosis: molecular regulation of cell death. Eur J Biochem 236:1–26CrossRefGoogle Scholar
  17. Ho JW, Hon PN, Chim WO (2009) Effects of oxymatrine from Ku Shen on cancer cells. Anticancer Agents Med Chem 9:823–826CrossRefGoogle Scholar
  18. 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 25:195–201Google Scholar
  19. 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 104:15–26CrossRefGoogle Scholar
  20. Khan SA, Toledano MB, Taylor-Robinson SD (2008) Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB 10:77–82CrossRefGoogle Scholar
  21. 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 28:637–638Google Scholar
  22. 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 30:1–8Google Scholar
  23. 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 12:145–151Google Scholar
  24. 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 13:1223–1227Google Scholar
  25. 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 13:1–9CrossRefGoogle Scholar
  26. Liu Y, Xu Y, Ji WD (2014) Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol 3:5111–5119CrossRefGoogle Scholar
  27. Miller G, Jarnagin WR (2008) Gallbladder carcinoma. Eur J Surg Oncol 34:306–312CrossRefGoogle Scholar
  28. Orrenius S (2006) Mitochondrial regulation of apoptotic cell death. Toxicol Lett 149:19–23CrossRefGoogle Scholar
  29. Pan L, Chai H, Kinghorn AD (2010) The continuing search for antitumor agents from higher plants. Phytochem Lett 3:1–8CrossRefGoogle Scholar
  30. Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279–296CrossRefGoogle Scholar
  31. Qin X, Yin J, Zhang H (2009) Effects of oxymatrine on proliferation of HepG2 cells. China J Chin Mater Med 34:1426–1429Google Scholar
  32. Shao Q (2011) The recent effect of radiotherapy combined with compound kushen injection for esophageal cancer. Radiother Oncol 99:S372–S373CrossRefGoogle Scholar
  33. 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 28:4581–4586CrossRefGoogle Scholar
  34. 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 70:2747–2753CrossRefGoogle Scholar
  35. 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 13:1788–1793CrossRefGoogle Scholar
  36. 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 2012:373219Google Scholar
  37. 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 9:178–188Google Scholar
  38. 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 528:261–266CrossRefGoogle Scholar
  39. 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 89:2116–2121CrossRefGoogle Scholar
  40. Valeriote F, Corbett T, Lorusso P, Moore RE, Scheuer P, Patterson G (2015) Anticancer agents from natural products. Pharm Biol 33:59–66CrossRefGoogle Scholar
  41. 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 89:227–231CrossRefGoogle Scholar
  42. 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 63:775–782CrossRefGoogle Scholar
  43. 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 33:1475–1483CrossRefGoogle Scholar
  44. 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 140:749–755CrossRefGoogle Scholar
  45. Yun SJ, Kim WJ (2013) Role of the epithelial–mesenchymal transition in bladder cancer: from prognosis to therapeutic target. Korean J Urol 54:645–650CrossRefGoogle Scholar
  46. 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 59:191–200CrossRefGoogle Scholar
  47. 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:e46853CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Department of General SurgeryWujiang No.1 People’s HospitalSuzhouChina
  2. 2.Department of Gynaecology and ObstetricsHealth Center of SonglingSuzhouChina

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