Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
November-2018 Volume 42 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
November-2018 Volume 42 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK

  • Authors:
    • Seulki Lee
    • Young Youn Cho
    • Eun Ju Cho
    • Su Jong Yu
    • Jeong‑Hoon Lee
    • Jung‑Hwan Yoon
    • Yoon Jun Kim
  • View Affiliations / Copyright

    Affiliations: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea
    Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2551-2559
    |
    Published online on: August 3, 2018
       https://doi.org/10.3892/ijmm.2018.3807
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Sorafenib has been approved for the treatment of advanced stage hepatocellular carcinoma but has limited efficacy. Ursodeoxycholic acid exerts cytoprotective activities in hepatocytes and is believed to suppress tumorigenesis through cell cycle arrest and induction of apoptosis. The present study examined whether co‑treatment with ursodeoxycholic acid has a synergistic effect on the antitumor activity of sorafenib in hepatocellular carcinoma cells. Notably, co‑treatment with both agents more effectively inhibited cell proliferation than sorafenib or ursodeoxycholic acid alone. Furthermore, co‑treatment inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activated extracellular signal‑regulated kinase (ERK), a mitogen‑activated protein kinase, accompanied by excessive intracellular reactive oxygen species generation in hepatocellular carcinoma cells. Thus, chemotherapy with sorafenib and ursodeoxycholic combination may be efficacious in hepatocellular carcinoma by inhibiting cell proliferation and inducing apoptosis through reactive oxygen species‑dependent activation of ERK and dephosphorylation of STAT3. The present findings may represent a promising therapeutic strategy for patients with advanced hepatocellular carcinoma.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar

2 

Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar

4 

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin SK, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepato-cellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar

5 

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

6 

Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Almhanna K and Philip PA: Safety and efficacy of sorafenib in the treatment of hepatocellular carcinoma. Onco Targets Ther. 2:261–267. 2009.PubMed/NCBI

8 

Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C, Oliveri F, Bartolozzi C and Ricci S: Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 69:773–780. 2012. View Article : Google Scholar

9 

Wang L, Jia D, Duan F, Sun Z, Liu X, Zhou L, Sun L, Ren S, Ruan Y and Gu J: Combined anti-tumor effects of IFN-α and sorafenib on hepatocellular carcinoma in vitro and in vivo. Biochem Biophys Res Commun. 422:687–692. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Yang Y, Jiang H, Gao H, Kong J, Zhang P, Hu S, Shi B, Zhang P, Yao M and Li Z: The monoclonal antibody CH12 enhances the sorafenib-mediated growth inhibition of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III. Neoplasia. 14:509–518. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Greim H, Trülzsch D, Roboz J, Dressler K, Czygan P, Hutterer F, Schaffner F and Popper H: Mechanism of cholestasis. 5. Bile acids in normal rat livers and in those after bile duct ligation. Gastroenterology. 63:837–845. 1972.PubMed/NCBI

12 

Alberts DS, Martinez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, Guillen J, Krutzsch M, Batta AK, Salen G, et al: Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 97:846–853. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Loddenkemper C, Keller S, Hanski ML, Cao M, Jahreis G, Stein H, Zeitz M and Hanski C: Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid. Int J Cancer. 118:2750–2757. 2006. View Article : Google Scholar

14 

Sabharwal SS and Schumacker PT: Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 14:709–721. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Tan BJ and Chiu GN: Role of oxidative stress, endoplasmic reticulum stress and ERK activation in triptolide-induced apoptosis. Int J Oncol. 42:1605–1612. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Chen J, Wang J, Lin L, He L, Wu Y, Zhang L, Yi Z, Chen Y, Pang X and Liu M: Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther. 11:277–287. 2012. View Article : Google Scholar

17 

Ryu K, Susa M, Choy E, Yang C, Hornicek FJ, Mankin HJ and Duan Z: Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer. 10:1872010. View Article : Google Scholar : PubMed/NCBI

18 

Wake MS and Watson CJ: STAT3 the oncogene-still eluding therapy? FEBS J. 282:2600–2611. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Gu FM, Li QL, Gao Q, Jiang JH, Huang XY, Pan JF, Fan J and Zhou J: Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol. 17:3922–3932. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Blechacz BR, Smoot RL, Bronk SF, Werneburg NW, Sirica AE and Gores GJ: Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2. Hepatology. 50:1861–1870. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Nordberg J and Arner ES: Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med. 31:1287–1312. 2001. View Article : Google Scholar : PubMed/NCBI

22 

Circu ML and Aw TY: Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 48:749–762. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Lim SC, Duong HQ, Choi JE, Lee TB, Kang JH, Oh SH and Han SI: Lipid raft-dependent death receptor 5 (DR5) expression and activation are critical for ursodeoxycholic acid-induced apoptosis in gastric cancer cells. Carcinogenesis. 32:723–731. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Coriat R, Nicco C, Chereau C, Mir O, Alexandre J, Ropert S, Weill B, Chaussade S, Goldwasser F and Batteux F: Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther. 11:2284–2293. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Park BH, Lim JE, Jeon HG, Seo SI, Lee HM, Choi HY, Jeon SS and Jeong BC: Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2. Oncotarget. 7:63870–63886. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Zuo D, Zhou Z, Wang H, Zhang T, Zang J, Yin F, Sun W, Chen J, Duan L, Xu J, et al: Alternol, a natural compound, exerts an anti-tumour effect on osteosarcoma by modulating of STAT3 and ROS/MAPK signalling pathways. J Cell Mol Med. 21:208–221. 2017. View Article : Google Scholar

27 

Pang L, Zhao X, Liu W, Deng J, Tan X and Qiu L: Anticancer effect of ursodeoxycholic acid in human oral squamous carcinoma HSC-3 cells through the caspases. Nutrients. 7:3200–3218. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G and Kouroumalis EA: A concentration-dependent effect of ursodeoxycholate on apoptosis and caspases activities of HepG2 hepatocellular carcinoma cells. Eur J Pharmacol. 640:1–7. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Krishna-Subramanian S, Hanski ML, Loddenkemper C, Choudhary B, Pagès G, Zeitz M and Hanski C: UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation. Int J Cancer. 130:2771–2782. 2012. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Lee S, Cho YY, Cho EJ, Yu SJ, Lee JH, Yoon JH and Kim YJ: Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. Int J Mol Med 42: 2551-2559, 2018.
APA
Lee, S., Cho, Y.Y., Cho, E.J., Yu, S.J., Lee, J., Yoon, J., & Kim, Y.J. (2018). Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. International Journal of Molecular Medicine, 42, 2551-2559. https://doi.org/10.3892/ijmm.2018.3807
MLA
Lee, S., Cho, Y. Y., Cho, E. J., Yu, S. J., Lee, J., Yoon, J., Kim, Y. J."Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK". International Journal of Molecular Medicine 42.5 (2018): 2551-2559.
Chicago
Lee, S., Cho, Y. Y., Cho, E. J., Yu, S. J., Lee, J., Yoon, J., Kim, Y. J."Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK". International Journal of Molecular Medicine 42, no. 5 (2018): 2551-2559. https://doi.org/10.3892/ijmm.2018.3807
Copy and paste a formatted citation
x
Spandidos Publications style
Lee S, Cho YY, Cho EJ, Yu SJ, Lee JH, Yoon JH and Kim YJ: Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. Int J Mol Med 42: 2551-2559, 2018.
APA
Lee, S., Cho, Y.Y., Cho, E.J., Yu, S.J., Lee, J., Yoon, J., & Kim, Y.J. (2018). Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK. International Journal of Molecular Medicine, 42, 2551-2559. https://doi.org/10.3892/ijmm.2018.3807
MLA
Lee, S., Cho, Y. Y., Cho, E. J., Yu, S. J., Lee, J., Yoon, J., Kim, Y. J."Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK". International Journal of Molecular Medicine 42.5 (2018): 2551-2559.
Chicago
Lee, S., Cho, Y. Y., Cho, E. J., Yu, S. J., Lee, J., Yoon, J., Kim, Y. J."Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK". International Journal of Molecular Medicine 42, no. 5 (2018): 2551-2559. https://doi.org/10.3892/ijmm.2018.3807
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team