Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells

  • Authors:
    • Guofang Chen
    • Diana Nicula
    • Kostja Renko
    • Michael Derwahl
  • View Affiliations

  • Published online on: February 16, 2015     https://doi.org/10.3892/or.2015.3805
  • Pages: 1994-2000
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Sorafenib, a multikinase inhibitor has recently been approved for the treatment of radio-iodine refractory thyroid carcinoma. However, toxic side effects may lead to dose reduction. In the present study, we analyzed whether a combined therapy with metformin may allow a dose reduction of sorafenib without loss of effectiveness at the same time. In HTh74 anaplastic thyroid carcinoma (ATC) cells and its derived doxorubicin-resistant HTh74Rdox cell line, the growth inhibitory effect of sorafenib with or without metformin was investigated. Furthermore, an analysis of cell cycle arrest in response to sorafenib was performed and the ability of a combined treatment to induce apoptosis was analyzed. In addition, the effects on clonal growth and formation of stem cell-derived spheres were assayed. The influence of sorafenib and metformin on MAP kinase pathway was investigated by analysis of ERK phosphorylation. Sorafenib and metformin synergistically inhibited growth of the two thyroid cancer cell lines, with a more pronounced effect on the doxorubicin-resistant HTh74Rdox cell line. The two drugs also synergistically decreased sphere formation, which suggested a specific effect on thyroid cancer stem cells. The addition of metformin enabled a 25% dose reduction of sorafenib without loss of its growth inhibitory efficacy. Sorafenib and metformin synergistically decreased the proliferation of ATC cell lines and the outgrowth of their derived cancer stem cells. A combined treatment enabled a significant dose reduction of sorafenib. In respect to frequent toxic side effects, clinical studies in future should demonstrate whether the addition of metformin may be an advantage in the chemotherapy of patients with radio-iodine‑resistant thyroid cancer.

References

1 

Ordonez N, Baloch Z, Matias-Guiu X, et al: Undifferentiated (anaplastic) carcinoma. World Health Organization Classification of Tumours of Endocrine Organs. DeLellis RA, Lloyd RV, Heitz PU and Eng C: IARC Press; Lyons: pp. 77–80. 2004

2 

Smallridge RC, Marlow LA and Copland JA: Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 16:17–44. 2009. View Article : Google Scholar

3 

Pasieka JL: Anaplastic thyroid cancer. Curr Opin Oncol. 15:78–83. 2003. View Article : Google Scholar

4 

Granata R, Locati L and Licitra L: Therapeutic strategies in the management of patients with metastatic anaplastic thyroid cancer: review of the current literature. Curr Opin Oncol. 25:224–228. 2013.PubMed/NCBI

5 

Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM and Lynch M: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 7:3129–3140. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Brose MS, Nutting CM, Jarzab B, et al: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 384:319–328. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Gupta-Abramson V, Troxel AB, Nellore A, et al: Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 26:4714–4719. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Haugen BR and Kane MA: Approach to the thyroid cancer patient with extracervical metastases. J Clin Endocrinol Metab. 95:987–993. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Savvides P, Nagaiah G, Lavertu P, et al: Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid. 23:600–604. 2013. View Article : Google Scholar :

10 

Duntas LH and Bernardini R: Sorafenib: rays of hope in thyroid cancer. Thyroid. 20:1351–1358. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Chen G, Xu S, Renko K and Derwahl M: Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 97:E510–E520. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Zheng X, Cui D, Xu S, Brabant G and Derwahl M: Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: Characterization of resistant cells. Int J Oncol. 37:307–315. 2010.PubMed/NCBI

13 

Broecker M, Hammer J and Derwahl M: Excessive activation of tyrosine kinases leads to inhibition of proliferation in a thyroid carcinoma cell line. Life Sci. 63:2373–2386. 1998. View Article : Google Scholar

14 

Manole D, Schildknecht B, Gosnell B, Adams E and Derwahl M: Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms. J Clin Endocrinol Metab. 86:1072–1077. 2001.PubMed/NCBI

15 

Isakovic A, Harhaji L, Stevanovic D, et al: Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci. 64:1290–1302. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Lan L, Cui D, Nowka K and Derwahl M: Stem cells derived from goiters in adults form spheres in response to intense growth stimulation and require thyrotropin for differentiation into thyrocytes. J Clin Endocrinol Metab. 92:3681–3688. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Reddi HV, Madde P, McDonough SJ, et al: Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy. Cancer Gene Ther. 19:659–665. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Thomas L, Lai SY, Dong W, et al: Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist. 19:251–258. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Wilhelm SM, Carter C, Tang L, 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

20 

Salvatore G, De Falco V, Salerno P, et al: BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res. 12:1623–1629. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit JW and Kapiteijn E: Long-term analysis of the efficacy and tolerability of sorafenib in advanced radioiodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol. 167:643–650. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Kim S, Yazici YD, Calzada G, et al: Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 6:1785–1792. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Henderson YC, Ahn SH, Kang Y and Clayman GL: Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Clin Cancer Res. 14:4908–4914. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Shen CT, Qiu ZL and Luo QY: Sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer: a meta-analysis. Endocr Relat Cancer. 21:253–261. 2014. View Article : Google Scholar

25 

Mitsutake N, Iwao A, Nagai K, et al: Characterization of side population in thyroid cancer cell lines: cancer stem-like cells are enriched partly but not exclusively. Endocrinology. 148:1797–1803. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Ling S, Feng T, Ke Q, et al: Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines. Oncol Rep. 31:2611–2618. 2014.PubMed/NCBI

Related Articles

Journal Cover

April 2015
Volume 33 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Chen, G., Nicula, D., Renko, K., & Derwahl, M. (2015). Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells. Oncology Reports, 33, 1994-2000. https://doi.org/10.3892/or.2015.3805
MLA
Chen, G., Nicula, D., Renko, K., Derwahl, M."Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells". Oncology Reports 33.4 (2015): 1994-2000.
Chicago
Chen, G., Nicula, D., Renko, K., Derwahl, M."Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells". Oncology Reports 33, no. 4 (2015): 1994-2000. https://doi.org/10.3892/or.2015.3805