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01-11-2013 | Original article

Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

Authors: Dr. C. Blattmann, M.D., M. Thiemann, PhD, A. Stenzinger, M.D., A. Christmann, M.D., E. Roth, M.D., V. Ehemann, PhD, J. Debus, A.E. Kulozik, W. Weichert, P.E. Huber, S. Oertel, M.D., A. Abdollahi, M.D.

Published in: Strahlentherapie und Onkologie | Issue 11/2013

Abstract

Background

Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo.

Methods

Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling.

Results

Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis.

Conclusion

Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.

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Belka C, Marini P, Budach W et al (1998) Radiation-induced apoptosis in human lymphocytes and lymphoma cells critically relies on the up-regulation of CD95/Fas/APO-1 ligand. Radiat Res 149:588–595PubMedCrossRef

Bellarosa D, Bressan A, Bigioni M et al (2012) SAHA/Vorinostat induces the expression of the CD137 receptor/ligand system and enhances apoptosis mediated by soluble CD137 receptor in a human breast cancer cell line. Int J Oncol41:1486–1494

Bielack S, Jürgens H, Jundt G et al (2009) Osteosarcoma: the COSS experience. Cancer Treat Res 152:289–308PubMedCrossRef

Bielack SS, Carrle D, Hardes J et al (2008) Bone tumors in adolescents and young adults. Curr Treat Options Oncol 9:67–80PubMedCrossRef

Bielack SS, Kempf-Bielack B, Delling G et al (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776–790PubMedCrossRef

Blattmann C, Oertel S, Ehemann V et al (2010) Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 78:237–245PubMedCrossRef

Blattmann C, Oertel S, Thiemann M et al (2012) Suberoylanilide hydroxamic acid affects γH2AX expression in osteosarcoma, atypical teratoid rhabdoid tumor and normal tissue cell lines after irradiation. Strahlenther Onkol 188:168–176PubMedCrossRef

Bots M, Johnstone RW (2009) Rational combinations using HDAC inhibitors. Clin Cancer Res 15:3970–3977PubMedCrossRef

Bridges KA, Hirai H, Buser CA et al (2011) MK-1775, a novel wee1 kinase inhibitor radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17:5638–5648PubMedCrossRef

10.

Dickinson M, Johnstone RW, Prince HM (2012) Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs 28(Suppl 1):S3–S20CrossRef

11.

Robert C, Rassool FV (2012) HDAC inhibitors: roles of DNA damage and repair. Adv Cancer Res 116:87–129PubMed

12.

Eckner R (2012) p53-dependent growth arrest and induction of p21: a critical role for PCAF-mediated histone acetylation. Cell Cycle 11:2591–2592PubMedCrossRef

13.

Ellis L, Hammers H, Pili R (2009) Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 280:145–153PubMedCrossRef

14.

Entin-Meer M, Yang X, Vandenburg SR et al (2007) In vivo efficacy of a novel histone deacetylase inhibitor in combination with radiation for the treatment of gliomas. Neuro Oncol 9:82–88PubMedCrossRef

15.

Folkvord S, Ree AH, Furre T et al (2009) Radiosensitization by SAHA in experimental colorectal carcinoma models—in vivo effects and relevance of histone acetylation status. Int J Radiat Oncol Biol Phys 74:546–552PubMedCrossRef

16.

Greve B, Sheikh-Mounessi F, Kemper B et al (2012) Survivin, a target to modulate the radiosensitivity of Ewing’s sarcoma. Strahlenther Onkol 188(11):1038–1047PubMedCrossRef

17.

Frew AJ, Johnstone RW, Bolden JE (2009) Enhancing the apoptotic and therapeutic effects of HDAC inhibitors. Cancer Lett 125:280–233

18.

Fuchs EJ, McKenna KA, Bedi A (1997) p53-dependent DNA-damage-induced apoptosis requires Fas/APO-1-independent activation of CPP32β. Cancer Res 57:2550–2554PubMed

19.

Hundsdoerfer P, Albrecht M, Rühl U et al (2009) Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma. Eur J Cancer 45:2447–2451PubMedCrossRef

20.

Johnstone RW, Licht JD (2003) Histone seacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4:13–18PubMedCrossRef

21.

Kawano T, Akiyama M, Agawa-Ohta M et al (2010) Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. Int J Oncol 37:787–795PubMed

22.

Koshkina NV, Rao-Bindal K, Kleinermann ES (2011) Effect of the HDAC inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metafase. Cancer 117:3457–3467PubMedCrossRef

23.

Langenbacher M, Abdel-Jalil RJ, Voelter W et al (2013) In vitro hypoxic cytotoxicity and hypoxic radiosensitization: efficacy of the novel 2-nitroimidazole N,N,N-tris[2-(2-nitro-1H-imidazol-1-yl)ethyl]amine. Strahlenther Onkol 189:246–255PubMedCrossRef

24.

Ma X, Ezzeldin HH, Diaso RB (2009) Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 69:1911–1934PubMedCrossRef

25.

Mottet D, Castronovo V (2010) Histone deacetylases: anti-angiogenic targets in cancer therapy. Curr Cancer Drug Targets 10:898–913PubMedCrossRef

26.

Müller M, Wilder S, Bannasch D et al (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188:2033–2045PubMedCrossRef

27.

Munshi A, Kurland JF, Nishikawa T et al (2005) Histone deacetylase inhibitors radiosensitize human melanoma by suppressing DNA repair activity. Clin Cancer Res 11:4912–4922PubMedCrossRef

28.

New M, Olzscha H, La Thangue NB (2012) HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol 6:637–656PubMedCrossRef

29.

Oertel S, Thiemann M, Richter K et al (2011) Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines. Radiat Oncol 20:119CrossRef

30.

Robert C, Rassool FV (2012) HDAC inhibitors: roles of DNA damage and repair. Adv Cancer Res 116:87–129PubMed

31.

Romano JW, Ehrhart JC, Duthu A et al (1989) Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. Oncogene 4(12):1483–1488PubMed

32.

Schuchmann M, Schulze-Bergkamen H, Fleischer B et al (2006) Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. Oncol Rep 15:227–230PubMed

33.

Shabason JE, Tofilon PJ, Camphausen K (2011) Grand rounds at the national institutes of health: HDAC inhibitors as radiation modifiers, from bench to clinic. J Cell Mol Med 15:2735–2744PubMedCrossRef

34.

Tamura T, Aoyama H, Saya H et al (1995) Induction of Fas-mediated apoptosis in p53-transfected human colon carcinoma cells. Oncogene 11:1939–1946PubMed

35.

Thayanithy V, Park C, Sarver AL et al (2012) Combinatorial treatment of DNA and chromatin-modifying drugs cause cell death in human and canine osteosarcoma cell lines. PLoS One 7:e43720PubMedCrossRef

36.

Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedCrossRef

37.

Watanabe K, Okamoto K, Yonehara S (2005) Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ 12:10–18PubMedCrossRef

38.

Xargay-Torrent S, López-Guerra M, Saborit-Villarroya I et al (2011) Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters. Clin Cancer Res 15:17:3956–3968

39.

Zhao Y, Lu S, Wu L et al (2006) Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21[Waf1/Cip1]. Mol Cell Biol 26:2782–2790PubMedCrossRef

Title: Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model
Authors: Dr. C. Blattmann, M.D.
M. Thiemann, PhD
A. Stenzinger, M.D.
A. Christmann, M.D.
E. Roth, M.D.
V. Ehemann, PhD
J. Debus
A.E. Kulozik
W. Weichert
P.E. Huber
S. Oertel, M.D.
A. Abdollahi, M.D.
Publication date: 01-11-2013
Publisher: Springer Berlin Heidelberg
Published in: Strahlentherapie und Onkologie / Issue 11/2013
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-013-0372-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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