Skip to main content
SpringerLink
Log in

Sunitinib Reverse Multidrug Resistance in Gastric Cancer Cells by Modulating Stat3 and Inhibiting P-gp Function

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, has been applied in phase II clinical trial as second-line treatment for advanced gastric cancer. In this study, we determined the effect of Sunitinib on the multidrug resistance in gastric cancer cells selected by vincristine. Our results showed that Sunitinib significantly enhanced the cytotoxicity of adriamycin, vincristine, etoposide, 5-Fluorouracil, and cisplatin in multidrug-resistant gastric cancer cells (SGC7901/VCR). Sunitinib significantly increased the intracellular accumulation and retention of rhodamine 123 in the SGC7901/VCR cells. However, Sunitinib, at a concentration that reverses MDR, had no significant effect on P-gp protein or mRNA expression levels. In addition, the present study revealed that Sunitinib inhibited Stat3 and down-regulated Bcl-2 in SGC7901/VCR cells, which might also contribute to the reversal of MDR. In conclusion, Sunitinib reverses multidrug resistance in gastric cancer cells by inhibiting P-gp transporter function and modulating Stat3 and Bcl-2. Further study with Sunitinib may be helpful for developing combination therapeutic strategy or circumventing gastric cancer MDR to other conventional anti-cancer drugs.

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

Similar content being viewed by others

References

  1. Murray, C. J., & Lopez, A. D. (1997). Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study. Lancet, 349, 1498–1504.

    Article  PubMed  CAS  Google Scholar 

  2. Cunningham, D., Allum, W. H., Stenning, S. P., Thompson, J. N., Van de Velde, C. J., Nicolson, M., et al. (2006). Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New England Journal of Medicine, 355, 11–20.

    Article  PubMed  CAS  Google Scholar 

  3. Rivera, F., Vega-Villegas, M. E., & Lopez-Brea, M. F. (2007). Chemotherapy of advanced gastric cancer. Cancer Treatment Reviews, 33, 315–324.

    Article  PubMed  CAS  Google Scholar 

  4. Szakacs, G., Paterson, J. K., Booth-Genthe, C., & Gottesman, M. M. (2006). Targeting multidrug resistance in cancer. Nature Reviews Drug Discovery, 5, 219–234.

    Article  PubMed  CAS  Google Scholar 

  5. Hong, L., Piao, Y., Han, Y., Wang, J., Zhang, X., Du, Y., et al. (2005). Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. Molecular Cancer Therapeutics, 4, 1936–1942.

    Article  PubMed  CAS  Google Scholar 

  6. Zhu, W., Xu, H., Zhu, D., Zhi, H., Wang, T., Wang, J., et al. (2012). miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP. Cancer Chemotherapy and Pharmacology, 69, 723–731.

    Article  PubMed  CAS  Google Scholar 

  7. Xia, L., Zhang, D., Du, R., Pan, Y., Zhao, L., Sun, S., et al. (2008). miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. International Journal of Cancer, 123, 372–379.

    Article  CAS  Google Scholar 

  8. Huang, S., Chen, M., Shen, Y., Shen, W., Guo, H., Gao, Q., et al. (2012). Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. Cancer Letters, 315, 198–205.

    Article  PubMed  CAS  Google Scholar 

  9. Hu, W. Q., Peng, C. W., & Li, Y. (2009). The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer. Journal of Experimental and Clinical Cancer Research, 28, 144–149.

    Article  PubMed  Google Scholar 

  10. Abrams, T. J., Lee, L. B., Murray, L. J., Pryer, N. K., & Cherrington, J. M. (2003). SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Molecular Cancer Therapeutics, 2, 471–478.

    PubMed  CAS  Google Scholar 

  11. Pan, F., Tian, J., Zhang, X. C., & Pan, Y. Y. (2010). Inhibitory effect of sunitinib on EGFR TKI-resistant humannon-small cell lung cancer cell line A549 and its mechanism. Chinese Pharmacological Bulletin, 8, 91–95.

    Google Scholar 

  12. Anglesio, M. S., George, J., & Kulbe, H. (2011). IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clinical Cancer Research, 17, 2538.

    Article  PubMed  CAS  Google Scholar 

  13. Saito, Y., Tanaka, Y., & Aita, Y. (2012). Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD. American Journal Physiology Endocrinology Metabolism, 302, E615–E625.

    Article  CAS  Google Scholar 

  14. Shukla, S., Robey, R. W., Bates, S. E., & Ambudkar, S. V. (2008). Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metabolism and Disposition, 37, 359–365.

    Article  PubMed  Google Scholar 

  15. Dai, C. L., Liang, Y. J., Wang, Y. S., et al. (2009). Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Letters, 279, 74–83.

    Article  PubMed  CAS  Google Scholar 

  16. Cai, X. J., Fan, D. M., & Zhang, X. Y. (1994). Establishment and biological characteristics of MDR human gastric cancer cell line. Chinese Journal of Clinical Oncology, 2, 67–71.

    Google Scholar 

  17. Chen, L. M., Wu, X. P., Ruan, J. W., et al. (2004). Screening novel, potent multidrugresistant modulators from imidazole derivatives. Oncology Research, 14, 355–362.

    PubMed  CAS  Google Scholar 

  18. Morgillo, F., Martinelli, E., Troiani, T., Orditura, M., De Vita, F., & Ciardiello, F. (2011). Antitumor activity of sorafenib in human cancer cell lines with acquired resistance to EGFR and VEGFR tyrosine kinase inhibitors. PLoS ONE, 6, e28841.

    Article  PubMed  CAS  Google Scholar 

  19. Guo, X. L., Ma, N. N., Wang, J., Song, J. R., Bu, X. X., Cheng, Y., et al. (2008). Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer, 8, 375.

    Article  PubMed  Google Scholar 

  20. Wang, T. C., Wei, J. Z., Guo, C. S., Zhang, H. B., & Fan, H. X. (2010). Design, synthesis and anti-proliferative studies of a novel series of indirubin derivatives. Chinese Chemical Letters, 21, 1407–1410.

    Article  CAS  Google Scholar 

  21. Zhang, Y. F., Shi, Y. Q., Li, X. H., Du, R., Luo, G. H., Xia, L., et al. (2008). Proteasome inhibitor MG132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp. Cancer Biology and Therapy, 7, 540–546.

    Article  PubMed  CAS  Google Scholar 

  22. Xin, H., Zhang, C. Y., & Herrmann, A. (2009). Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Research, 69, 2506–2513.

    Article  PubMed  CAS  Google Scholar 

  23. Di Lauro, L., Giacinti, L., Arena, M. G., Sergi, D., Fattoruso, S. I., Giannarelli, D., et al. (2009). Phase II study of epirubicin, oxaliplatin and docetaxel combination in metastatic gastric or gastroesophageal junction adenocarcinoma. Journal of Experimental and Clinical Cancer Research, 28, 34–39.

    Article  PubMed  Google Scholar 

  24. Gottesman, M. M., Fojo, T., & Bates, S. E. (2002). Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Reviews Cancer, 2, 48–58.

    Article  PubMed  CAS  Google Scholar 

  25. Chen, Q., Zhou, J., Jiang, C. F., & Chen, J. (2010). Reversal of P-glycoprotein-mediated multidrug resistance in SGC7901/VCR cells by PPARγ activation by troglitazone. Journal of Huazhong University of Science and Technology, 30, 326–331.

    Article  PubMed  CAS  Google Scholar 

  26. Zhang, Y., Qu, X. J., Liu, Y. P., Yang, X. H., Hou, K. Z., Teng, Y. E., et al. (2009). Reversal effect of PI3-K inhibitor LY294002 on P-glycoprotein mediated multidrug resistance of human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR. Chinese Journal of Cancer, 28, 97–99.

    PubMed  Google Scholar 

  27. Zhu, W., Shan, X., Wang, T., Shu, Y., & Liu, P. (2010). miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. International Journal of Cancer, 127, 2520–2529.

    Article  CAS  Google Scholar 

  28. Fang, S., Zhu, W., Zhang, Y., Shu, Y., & Liu, P. (2012). Paeoniflorin modulates multidrug resistance of a human gastric cancer cell line via the inhibition of NF-κB activation. Molecular Medicine Reports, 5, 351–356.

    PubMed  CAS  Google Scholar 

  29. Coburger, C., Lage, H., Molnár, J., Langner, A., & Hilgeroth, A. (2010). Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors. Journal of Pharmacy and Pharmacology, 62, 1704–1710.

    Article  PubMed  CAS  Google Scholar 

  30. Bang, Y. J., Kang, Y. K., Kang, W. K., Boku, N., Chung, H. C., Chen, J. S., et al. (2011). Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Investigational New Drugs, 29, 1449–1458.

    Article  PubMed  CAS  Google Scholar 

  31. Lage, H. (2003). Molecular analysis of therapy resistance in gastric cancer. Digestive Diseases, 21, 326–338.

    Article  PubMed  Google Scholar 

  32. Mi, Y. J., Liang, Y. J., Huang, H. B., et al. (2010). Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Research, 70, 7981–7991.

    Article  PubMed  CAS  Google Scholar 

  33. Tao, L. Y., Liang, Y. J., Wang, F., Chen, L. M., Yan, Y. Y., Dai, C. L., et al. (2009). Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemotherapy and Pharmacology, 64, 961–969.

    Article  PubMed  CAS  Google Scholar 

  34. Santandreu, F. M., Valle, A., Oliver, J., & Roca, P. (2011). Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells. Cellular Physiology and Biochemistry, 28, 219–228.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Tumour Therapy Department with Western Medicine & Traditional Chinese Medicine, Wuxi No. 4 People’s Hospital, Wuxi Hospital of Oncology, The Fourth Affiliated Hospital of Soochow University, No. 200, Huihe Road, Wuxi, Jiangsu, 214062, China

    Ye Zhang

  2. Department of Oncology, Jiangyin Clinical Branch, Xuzhou Medical College, No. 163, Shoushan Road, Jiangyin, Jiangsu, 214400, China

    Qiong Wang

Authors
  1. Ye Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiong Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Wang, Q. Sunitinib Reverse Multidrug Resistance in Gastric Cancer Cells by Modulating Stat3 and Inhibiting P-gp Function. Cell Biochem Biophys 67, 575–581 (2013). https://doi.org/10.1007/s12013-013-9544-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-013-9544-5

Keywords

Search

Navigation