Simvastatin Enhances the Effects of Radiotherapy and Cetuximab on a Cell Line (FaDu) Derived from a Squamous Cell Carcinoma of Head and Neck

Overview

Journal Transl Oncol

Specialty Oncology

Date 2014 Aug 31

PMID 25171892

Citations 11

Authors

Lara I De Llobet

Marta Baro

Ricard Mesia

Josep Balart

Affiliations

Soon will be listed here.

Abstract

Radiotherapy (XRT) delivered with the antibody cetuximab is a standard treatment option for squamous cell carcinomas of head and neck (SCCNH). Cetuximab acts by blocking epidermal growth factor receptor (EGFR) signaling to inhibit cancer progression. However, a significant percentage of patients will not respond to XRT and cetuximab. Statins reduce the synthesis of cholesterol and isoprenoid derivates that may be required for efficient EGFR signaling. We assessed whether the statin simvastatin could improve this combined therapy. In vitro, simvastatin enhanced the effects of XRT alone and in combination with cetuximab in wound healing, cell proliferation, and clonogenic assays in FaDu cells. These results were reflected in xenoimplanted tumors growing into subcutaneous tissue of athymic mice where concomitant treatment with simvastatin decreased tumor growth. Consistently, lower levels of phosphorylated extracellular signal-regulated kinases 1 and 2, phosphatidylinositol 3-kinase/AKT-protein kinase B, and signal transducer and activator of transcription 3 oncoproteins and higher levels of caspase-3 and apoptosis in cell cultures and xenografts were observed. The EGFR-overexpressing A431 cell line was used to reproduce these antitumor effects of simvastatin. Our findings suggest that simvastatin may improve the efficiency of concomitant XRT and cetuximab. Further investigation in the treatment of SCCNH is warranted.

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References

Huang S, Bock J, Harari P . Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999; 59(8):1935-40. View

Kim W, Kim M, Choi H, Yoon S, Lee M, Park K . Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs. 2001; 19(1):81-3. DOI: 10.1023/a:1006481423298. View

Pueyo G, Mesia R, Figueras A, Lozano A, Baro M, Vazquez S . Cetuximab may inhibit tumor growth and angiogenesis induced by ionizing radiation: a preclinical rationale for maintenance treatment after radiotherapy. Oncologist. 2010; 15(9):976-86. PMC: 3228040. DOI: 10.1634/theoncologist.2008-0290. View

Werner M, Sacher J, Hohenegger M . Mutual amplification of apoptosis by statin-induced mitochondrial stress and doxorubicin toxicity in human rhabdomyosarcoma cells. Br J Pharmacol. 2004; 143(6):715-24. PMC: 1575923. DOI: 10.1038/sj.bjp.0705928. View

Freed-Pastor W, Mizuno H, Zhao X, Langerod A, Moon S, Rodriguez-Barrueco R . Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012; 148(1-2):244-58. PMC: 3511889. DOI: 10.1016/j.cell.2011.12.017. View

Dimitroulakos J, Ye L, Benzaquen M, Moore M, Kamel-Reid S, Freedman M . Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin Cancer Res. 2001; 7(1):158-67. View

Sleijfer S, van der Gaast A, Planting A, Stoter G, Verweij J . The potential of statins as part of anti-cancer treatment. Eur J Cancer. 2005; 41(4):516-22. DOI: 10.1016/j.ejca.2004.12.009. View

Nielsen S, Nordestgaard B, Bojesen S . Statin use and reduced cancer-related mortality. N Engl J Med. 2012; 367(19):1792-802. DOI: 10.1056/NEJMoa1201735. View

Vinals F, Chambard J, Pouyssegur J . p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J Biol Chem. 1999; 274(38):26776-82. DOI: 10.1074/jbc.274.38.26776. View

10.

Chan K, Oza A, Siu L . The statins as anticancer agents. Clin Cancer Res. 2003; 9(1):10-9. View

11.

Johnson-Anuna L, Eckert G, Keller J, Igbavboa U, Franke C, Fechner T . Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther. 2004; 312(2):786-93. DOI: 10.1124/jpet.104.075028. View

12.

Gauthaman K, Fong C, Bongso A . Statins, stem cells, and cancer. J Cell Biochem. 2009; 106(6):975-83. DOI: 10.1002/jcb.22092. View

13.

Wu H, Jiang H, Lu D, Xiong Y, Qu C, Zhou D . Effect of simvastatin on glioma cell proliferation, migration, and apoptosis. Neurosurgery. 2009; 65(6):1087-96. PMC: 3711082. DOI: 10.1227/01.NEU.0000360130.52812.1D. View

14.

Khanzada U, Pardo O, Meier C, Downward J, Seckl M, Arcaro A . Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling. Oncogene. 2005; 25(6):877-87. DOI: 10.1038/sj.onc.1209117. View

15.

Knox J, Siu L, Chen E, Dimitroulakos J, Kamel-Reid S, Moore M . A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer. 2005; 41(4):523-30. DOI: 10.1016/j.ejca.2004.12.013. View

16.

Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y . Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84(7):886-91. PMC: 2363838. DOI: 10.1054/bjoc.2000.1716. View

17.

Soma M, Pagliarini P, Butti G, Paoletti R, Paoletti P, Fumagalli R . Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells. Cancer Res. 1992; 52(16):4348-55. View

18.

Liang K, Ang K, Milas L, Hunter N, Fan Z . The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys. 2003; 57(1):246-54. DOI: 10.1016/s0360-3016(03)00511-x. View

19.

Baro M, De Llobet L, Modolell I, Guedea F, Visa J, Balart J . Development and refinement of a technique using a medical radiation therapy facility to irradiate immunodeficient mice bearing xenografted human tumours. Lab Anim. 2012; 46(4):345-8. DOI: 10.1258/la.2012.011147. View

20.

Lee J, Lee I, Han B, Park J, Jang J, Park C . Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst. 2011; 103(8):674-88. DOI: 10.1093/jnci/djr070. View