The mTOR inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy

Altmeyer,Anaïs; Josset,Elodie; Denis,Jean-Marc; Gueulette,John; Slabbert,Jakobus; Mutter,Didier; Noël,Georges; Bischoff,Pierre

doi:10.3892/ijo.2012.1583

The mTOR inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy

Authors:
- Anaïs Altmeyer
- Elodie Josset
- Jean-Marc Denis
- John Gueulette
- Jakobus Slabbert
- Didier Mutter
- Georges Noël
- Pierre Bischoff
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Affiliations: EA 3430, University of Strasbourg, Centre Paul Strauss, Strasbourg, France, MIRO, Catholic University of Louvain, Brussels, Belgium, iThemba LABS, Somerset West, South Africa, Research Institute against Digestive Cancer (IRCAD), Strasbourg, France
Published online on: August 7, 2012 https://doi.org/10.3892/ijo.2012.1583
Pages: 1381-1386

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Abstract

Treatment of hepatocellular carcinoma (HCC) is a major concern for physicians as its response to chemotherapy and radiotherapy remains generally poor, due, in part, to intrinsic resistance to either form of treatment. We previously reported that an irradiation with fast neutrons, which are high-linear energy transfer (LET) particles, massively induced autophagic cell death in the human HCC SK-Hep1 cell line. In the present study, we tested the capacity of the mammalian target of rapamycin (mTOR) inhibitor RAD001 to augment the cytotoxicity of low and high-LET radiation in these cells. As mTOR is a key component in a series of pathways involved in tumor growth and development, it represents a potential molecular target for cancer treatment. Results indicate that RAD001, at clinically relevant nanomolar concentrations, enhances the efficacy of both high- and low-LET radiation in SK-Hep1 cells, and that the induction of autophagy may account for this effect. However, fast neutrons were found to be more efficient at reducing tumor cell growth than low-LET radiation.

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1	Orecchia R, Krengli M, Jereczek-Fossa BA, Franzetti S and Gerard JP: Clinical and research validity of hadrontherapy with ion beams. Crit Rev Oncol Hematol. 51:81–90. 2004. View Article : Google Scholar : PubMed/NCBI
2	Finn RS: Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Cancer Res. 15:390–397. 2010. View Article : Google Scholar : PubMed/NCBI
3	Pommier P, Hu Y, Baron MH, Chapet O and Balosso J: Particle therapy: carbon ions. Bull Cancer. 97:819–829. 2010.PubMed/NCBI
4	Hamada N, Imaoka T, Masunaga S, et al: Recent advances in the biology of heavy-ion cancer therapy. J Radiat Res. 51:365–383. 2010. View Article : Google Scholar
5	Dumont F, Altmeyer A and Bischoff P: Radiosensitising agents for the radiotherapy of cancer: novel molecularly targeted approaches. Expert Opin Ther Pat. 19:775–799. 2009. View Article : Google Scholar : PubMed/NCBI
6	Begg AC, Stewart FA and Vens C: Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 11:239–253. 2011. View Article : Google Scholar : PubMed/NCBI
7	Abraham RT and Gibbons JJ: The mammalian target of rapamycin signaling pathway: twists and turns in the road of cancer therapy. Clin Cancer Res. 13:3109–3114. 2007. View Article : Google Scholar : PubMed/NCBI
8	Chiong E, Lee IL, Dadbin A, et al: Effects of mTOR inhibitor everolimus (RAD001) on bladder cancer cells. Clin Cancer Res. 17:2863–2873. 2011. View Article : Google Scholar : PubMed/NCBI
9	Dancey J: mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 7:209–219. 2010. View Article : Google Scholar : PubMed/NCBI
10	Kudo M: mTOR inhibitor for the treatment of hepatocellular carcinoma. Dig Dis. 29:310–315. 2011. View Article : Google Scholar : PubMed/NCBI
11	Gueulette J, Slabbert JP, Bischoff P, Denis JM, Wambersie A and Jones D: Fast neutrons: Inexpensive and reliable tool to investigate high-LET particle radiobiology. Rad Meas. 45:1414–1416. 2010. View Article : Google Scholar
12	Riccardi C and Nicoletti I: Analysis of apoptosis by propidium iodide staining and flow cytometry. Nature Protocols. 1:1458–1461. 2006. View Article : Google Scholar : PubMed/NCBI
13	Xu B, Wu Y, Shen L, et al: Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors. J Hematol Oncol. 13:4–3. 2001.PubMed/NCBI
14	Altmeyer A, Jung AC, Ignat M, et al: Pharmacological enhancement of autophagy induced in a hepatocellular carcinoma cell line by high-LET radiation. Anticancer Res. 30:303–310. 2010.PubMed/NCBI
15	Nyfeler B, Bergman P, Triantafellow E, et al: Relieving autophagy and 4EBP1 from rapamycin resistance. Mol Cell Biol. 31:2867–2876. 2011. View Article : Google Scholar : PubMed/NCBI
16	Rodriguez-Rocha H, Garcia-Garcia A, Panayiotidis MI and Franco R: DNA damage and autophagy. Mutat Res. 3:158–166. 2011. View Article : Google Scholar
17	Altmeyer A, Ignat M, Denis JM, Messaddeg N, Gueulette J, Mutter D and Bischoff P: Cell death after high-LET irradiation in orthotopic human hepatocellular carcinoma in vivo. In vivo. 25:1–9. 2011.PubMed/NCBI
18	Hada M and Georgakilas AG: Formation of clustered DNA damage after High-LET irradiation: a review. J Radiat Res. 49:203–210. 2008. View Article : Google Scholar : PubMed/NCBI
19	Benzina S, Altmeyer A, Malek F, et al: High-LET radiation combined with oxaliplatin induces autophagy in U-87 glioblastoma cells. Cancer Lett. 264:63–70. 2008. View Article : Google Scholar : PubMed/NCBI
20	Zois CE and Koukourakis MI: Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radiosensitization policies? Autophagy. 5:442–450. 2009. View Article : Google Scholar : PubMed/NCBI
21	Todde V, Veenhuis M and van der Klei IJ: Autophagy: Principles and significance in health and disease. Biochim Biophys Acta. 1792:3–13. 2009. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Wang LX, Pang P, et al: Tumor-derived autophagosomes vaccine: mechanism of cross-presentation and therapeutic efficacy. Clin Cancer Res. 17:7047–7057. 2001. View Article : Google Scholar : PubMed/NCBI
23	Takeshima T, Chamoto K, Wakita D, et al: Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res. 70:2697–2706. 2010. View Article : Google Scholar : PubMed/NCBI
24	Jabouin JJ, Shinohara ET, Moretti L, Yang ES, Kaminski JM and Lu B: The role of mTOR inhibition in augmenting radiation induced autophagy. Technol Cancer Res Treat. 6:443–447. 2007. View Article : Google Scholar : PubMed/NCBI
25	Saunders P, Cisterne A, Weiss J, Bradstock KF and Bendall LJ: The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. Haematologica. 96:69–77. 2011. View Article : Google Scholar
26	Sukumari-Ramesh S, Singh N, Dhandapani KM and Vender JR: mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surg Neurol Int. 2:222011. View Article : Google Scholar
27	Albert JM, Kim KW, Cao C and Lu B: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther. 5:1183–1189. 2006. View Article : Google Scholar : PubMed/NCBI
28	Kuwahara Y, Oikawa T, Ochiai Y, et al: Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy. Cell Deat Dis. 2:1–11. 2011.PubMed/NCBI
29	Eshleman JS, Carlson BL, Madek AC, Kastner AD, Shide L and Sarkaria JN: Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res. 15:7291–7297. 2002.PubMed/NCBI
30	Shinohara ET, Cao C, Niermann K, Mu Y, Zeng F, Hallahan DE and Lu B: Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene. 24:5414–5422. 2005. View Article : Google Scholar : PubMed/NCBI
31	Bandhakavi S, Kim YM, Ro SH, et al: Quantitative nuclear proteomics identifies mTOR regulation of DNA damage response. Mol Cell Proteomics. 9:403–414. 2010. View Article : Google Scholar : PubMed/NCBI
32	Tam KH, Yang ZF, Lam CT, Pang RW and Poon RT: Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. Cancer Lett. 273:201–209. 2009. View Article : Google Scholar : PubMed/NCBI
33	Chen H, Vanderwaal RP, Feng Z, et al: The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. Radiat Res. 175:214–224. 2011. View Article : Google Scholar : PubMed/NCBI
34	Zhu AX, Abrams TA, Miksad R, et al: Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer. 117:5094–5102. 2011. View Article : Google Scholar : PubMed/NCBI