Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib

  • Authors:
    • Yuezhao Huang
    • Kunyuan Wang
    • Chengxin Gu
    • Ganxiang Yu
    • Dan Zhao
    • Weijian Mai
    • Yun Zhong
    • Shiming Liu
    • Yuqiang Nie
    • Hui Yang
  • View Affiliations

  • Published online on: July 10, 2018     https://doi.org/10.3892/or.2018.6552
  • Pages: 1525-1532
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Abstract

Sorafenib resistance is one of the major factors affecting the prognosis of patients with hepatocellular carcinoma (HCC). Increasing evidence has indicated that certain traditional medicines can enhance the sensitivity of cancer cells to sorafenib. Berberine, an isoquinoline alkaloid, has been demonstrated to possess antitumor properties against various malignancies. However, the synergistic effect of the combination of berberine and sorafenib in HCC remains unknown. The aim of the present study was to determine the effects of berberine and sorafenib combination on the growth of liver cancer cells. Initially, it was observed that the combination of sorafenib and berberine exerted a synergistic inhibitory effect on the proliferation of SMMC‑7721 and HepG2 cells in a dose‑ and time‑dependent manner by an MTS assay. Edu staining and colony formation assays also revealed that the combination of 100 µM berberine and 4 µM sorafenib exhibited a significant anti‑proliferation effect on SMMC‑7721 and HepG2 cells. Furthermore, western blotting assay indicated that the expressions levels of cleaved poly(ADP‑ribose) polymerase and cleaved caspase‑3 increased, while those of the anti‑apoptotic protein B‑cell lymphoma 2 and vascular endothelial growth factor decreased. To the best of our knowledge, this is the first study to demonstrate that berberine sensitized liver cancer cells to sorafenib treatment. These results suggest that berberine combined with sorafenib is able to inhibit the proliferation of liver cancer cells and induce apoptosis, which provides evidence for further clinical investigation in HCC patients with sorafenib resistance.

References

1 

Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Sia D, Villanueva A, Friedman SL and Llovet JM: Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 152:745–761. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Dutta R and Mahato RI: Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther. 173:106–117. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Keating GM: Sorafenib: A review in hepatocellular carcinoma. Target Oncol. 12:243–253. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Finn RS, Zhu AX, Farah W, Almasri J, Zaiem F, Prokop LJ, Murad MH and Mohammed K: Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: A systematic review and meta-analysis. Hepatology. 67:422–435. 2017. View Article : Google Scholar

6 

Adnane L, Trail PA, Taylor I and Wilhelm SM: Sorafenib (BAY 43–9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 407:597–612. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R and Kelley S: Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 5:835–844. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Zhou C, Liu J, Li Y, Liu L, Zhang X, Ma CY, Hua SC, Yang M and Yuan Q: microRNA-1274a, a modulator of sorafenib induced a disintegrin and metalloproteinase 9 (ADAM9) down-regulation in hepatocellular carcinoma. Febs Lett. 585:1828–1834. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Potenza N, Mosca N, Zappavigna S, Castiello F, Panella M, Ferri C, Vanacore D, Giordano A, Stiuso P, Caraglia M and Russo A: MicroRNA-125a-5p is a downstream effector of sorafenib in its antiproliferative activity toward human hepatocellular carcinoma cells. J Cell Physiol. 232:1907–1913. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Chen J, Jin R, Zhao J, Liu J, Ying H, Yan H, Zhou S, Liang Y, Huang D, Liang X, et al: Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 367:1–11. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Alsaied OA, Sangwan V, Banerjee S, Krosch TC, Chugh R, Saluja A, Vickers SM and Jensen EH: Sorafenib and triptolide as combination therapy for hepatocellular carcinoma. Surgery. 156:270–279. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Li S, Dai W, Mo W, Li J, Feng J, Wu L, Liu T, Yu Q, Xu S, Wang W, et al: By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma. Int J Cancer. 141:2571–2584. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Ayati SH, Fazeli B, Momtazi-Borojeni AA, Cicero A, Pirro M and Sahebkar A: Regulatory effects of berberine on microRNome in Cancer and other conditions. Crit Rev Oncol Hematol. 116:147–158. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Tillhon M, Guaman OL, Lombardi P and Scovassi AI: Berberine: New perspectives for old remedies. Biochem Pharmacol. 84:1260–1267. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Li-Weber M: Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Lett. 332:304–312. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Tan W, Li Y, Chen M and Wang Y: Berberine hydrochloride: Anticancer activity and nanoparticulate delivery system. Int J Nanomedicine. 6:1773–1777. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Ruan H, Zhan YY, Hou J, Xu B, Chen B, Tian Y, Wu D, Zhao Y, Zhang Y, Chen X, et al: Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells. Oncogene. 36:6906–6918. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Wang J, Yang S, Cai X, Dong J, Chen Z, Wang R, Zhang S, Cao H, Lu D, Jin T, et al: Berberine inhibits EGFR signaling and enhances the antitumor effects of EGFR inhibitors in gastric cancer. Oncotarget. 7:76076–76086. 2016.PubMed/NCBI

19 

Li M, Zhang M, Zhang ZL, Liu N, Han XY, Liu QC, Deng WJ and Liao CX: Induction of apoptosis by berberine in hepatocellular carcinoma HepG2 cells via downregulation of NF-κB. Oncol Res. 25:233–239. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Ayati SH, Fazeli B, Momtazi-Borojeni AA, Cicero A, Pirro M and Sahebkar A: Regulatory effects of berberine on microRNome in Cancer and other conditions. Crit Rev Oncol Hematol. 116:147–158. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Wang XN, Han X, Xu LN, Yin LH, Xu YW, Qi Y and Peng JY: Enhancement of apoptosis of human hepatocellular carcinoma SMMC-7721 cells through synergy of berberine and evodiamine. Phytomedicine. 15:1062–1668. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Youn MJ, So HS, Cho HJ, Kim HJ, Kim Y, Lee JH, Sohn JS, Kim YK, Chung SY and Park R: Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biol Pharm Bull. 31:789–795. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Ueshima K, Kudo M, Tanaka M, Kumada T, Chung H, Hagiwara S, Inoue T, Yada N and Kitai S: Phase I/II study of sorafenib in combination with hepatic arterial infusion chemotherapy using low-dose cisplatin and 5-fluorouracil. Liver Cancer. 4:263–273. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Blivet-Van EM, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O and Desbois-Mouthon C: Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 57:108–115. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Zhang Z, Zhou X, Shen H, Wang D and Wang Y: Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: Evidence from an in vitro study. BMC Med. 7:412009. View Article : Google Scholar : PubMed/NCBI

27 

Yang X and Wu XZ: Main antitumor angiogenesis agents isolated from chinese herbal medicines. Mini Rev Med Chem. 15:1011–1023. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Lin M, Bi H, Yan Y, Huang W, Zhang G, Zhang G, Tang S, Liu Y, Zhang L, Ma J, et al: Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway. Oncotarget. 8:23436–23447. 2017.PubMed/NCBI

29 

He QL, Minn I, Wang Q, Xu P, Head SA, Datan E, Yu B, Pomper MG and Liu JO: Targeted delivery and sustained antitumor activity of triptolide through glucose conjugation. Angew Chem Int Ed Engl. 55:12035–12039. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Sun Y, Xun K, Wang Y and Chen X: A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs. 20:757–769. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Su K, Hu P, Wang X, Kuang C, Xiang Q, Yang F, Xiang J, Zhu S, Wei L and Zhang J: Tumor suppressor berberine binds VASP to inhibit cell migration in basal-like breast cancer. Oncotarget. 7:45849–45862. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Chen Q, Qin R, Fang Y and Li H: Berberine sensitizes human ovarian cancer cells to cisplatin through miR-93/PTEN/Akt signaling pathway. Cell Physiol Biochem. 36:956–965. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Bao J, Huang B, Zou L, Chen S, Zhang C, Zhang Y, Chen M, Wan JB, Su H, Wang Y and He C: Hormetic effect of berberine attenuates the anticancer activity of chemotherapeutic agents. PLoS One. 10:e1392982015. View Article : Google Scholar

34 

Hou D, Xu G, Zhang C, Li B, Qin J, Hao X, Liu Q, Zhang X, Liu J, Wei J, et al: Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition. Cell Death Dis. 8:e30702017. View Article : Google Scholar : PubMed/NCBI

35 

Das T, Sa G, Saha B and Das K: Multifocal signal modulation therapy of cancer: Ancient weapon targets. Mol Cell Biochem. 336:85–95. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Yu R, Zhang ZQ, Wang B, Jiang HX, Cheng L and Shen LM: Berberine-induced apoptotic and autophagic death of HepG2 cells requires AMPK activation. Cancer Cell Int. 14:492014. View Article : Google Scholar : PubMed/NCBI

37 

Fu L, Chen W, Guo W, Wang J, Tian Y, Shi D, Zhang X, Qiu H, Xiao X, Kang T, et al: Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and cytochrome-c/caspase signaling to suppress human cancer cell growth. PLoS One. 8:e692402013. View Article : Google Scholar : PubMed/NCBI

38 

Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI

39 

Wang H, Zhang C, Ning Z, Xu L, Zhu X and Meng Z: Bufalin enhances anti-angiogenic effect of sorafenib via AKT/VEGF signaling. Int J Oncol. 48:1229–12241. 2016. View Article : Google Scholar : PubMed/NCBI

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September 2018
Volume 40 Issue 3

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Copy and paste a formatted citation
APA
Huang, Y., Wang, K., Gu, C., Yu, G., Zhao, D., Mai, W. ... Yang, H. (2018). Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib. Oncology Reports, 40, 1525-1532. https://doi.org/10.3892/or.2018.6552
MLA
Huang, Y., Wang, K., Gu, C., Yu, G., Zhao, D., Mai, W., Zhong, Y., Liu, S., Nie, Y., Yang, H."Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib". Oncology Reports 40.3 (2018): 1525-1532.
Chicago
Huang, Y., Wang, K., Gu, C., Yu, G., Zhao, D., Mai, W., Zhong, Y., Liu, S., Nie, Y., Yang, H."Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib". Oncology Reports 40, no. 3 (2018): 1525-1532. https://doi.org/10.3892/or.2018.6552