Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Radiation Oncology
Published in: Radiation Oncology 1/2015

Open Access 01-12-2015 | Research

Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy

Authors: Claudia Blattmann, Susanne Oertel, Markus Thiemann, Anne Dittmar, Eva Roth, Andreas E. Kulozik, Volker Ehemann, Wilko Weichert, Peter E. Huber, Albrecht Stenzinger, Jürgen Debus

Published in: Radiation Oncology | Issue 1/2015

Login to get access

Abstract

Background

Minimal improvements in treatment or survival of patients with osteosarcoma have been achieved during the last three decades. Especially in the case of incomplete tumor resection, prognosis remains poor. Heavy ion radiotherapy (HIT) and modern anticancer drugs like histone deacetylase inhibitors (HDACi) have shown promising effects in osteosarcoma in vitro. In this study, we tested the effect of HIT and the combination of HIT and the HDACi suberoylanilide hydroxamic acid (SAHA) in a xenograft mouse model.

Methods

Osteosarcoma xenografts were established by subcutaneous injection of KHOS-24OS cells and treated with either vehicle (DMSO), SAHA, HIT or HIT and SAHA. Tumor growth was determined and tumor necrosis, proliferation rate, apoptotic rate as well as vessel density were evaluated.

Results

Here, we show that the combination of HIT and SAHA induced a significant delay of tumor growth through increased rate of apoptosis, increased expression of p53 and p21Waf1/Cip1, inhibition of proliferation and angiogenesis compared to tumors treated with HIT only.

Conclusion

HIT and in particular the combination of HIT and histone deacetylase inhibition is a promising treatment strategy in OS and may be tested in clinical trials.
Literature
1.
Schardt D, Elsässer T, Schulz-Ertner D. Heavy-ion tumor therapy: Physical and radio-biological benefits. Rev Mod Phys. 2010;82:383.CrossRef
2.
Hundsdoerfer P, Albrecht M, Rühl U, Fengler R, Kulozik AE, Henze G. Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma. Eur J Cancer. 2009;45(14):2447–51.PubMedCrossRef
3.
Blattmann C, Oertel S, Schulz-Ertner D, Rieken S, Haufe S, Ewerbeck V, et al. Non-randomized therapy trial to determine the safety and efficacy of heavy ion therapy in patients with non-resectable osteosarcomas. BMC Cancer. 2010;10:96.PubMedCentralPubMedCrossRef
4.
Sugahara S, Kamada T, Imai R, Tsuji H, Kameda N, Okada T, et al. Carbon ion radiotherapy for localized primary sarcoma of the extremities: results of a phase I/II trial. Working group for the bone and soft tissue sarcomas. Radiother Oncol. 2012;105(2):226–31.PubMedCrossRef
5.
Matsunobu A, Imai R, Kamada T, Imaizumi T, Tsuji H, Tsujii H, et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Working group for bone and soft tissue sarcomas. Cancer. 2012;118(18):4555–63.PubMedCrossRef
6.
Combs SE, Kessel KA, Herfarth K, Jensen A, Oertel S, Blattmann C, et al. Treatment of pediatric patients and young adults with particle therapy at the Heidelberg Ion Therapy Center (HIT): establishment of workflow and initial clinical data. Radiat Oncol. 2012;7:170.PubMedCentralPubMedCrossRef
7.
Perego P, Zuco V, Gatti L, Zunino F. Sensitization of tumor cells by targeting histone deacetylases. Biochem Pharmacol. 2012;83(8):987–94.PubMedCrossRef
8.
Entin-Meer M, Yang X, Vandenburg SR, Lamborn KR, Nudelman A, Rephaeli A, et al. In vivo efficacy of a novel histone deacetylase inhibitor in combination with radiation for the treatment of gliomas. Neuro Oncol. 2007;9:82–8.PubMedCentralPubMedCrossRef
9.
Folkvord S, Ree AH, Furre T, Halvorsen T, Flatmark K. Radiosensitization by SAHA in experimental colorectal carcinoma models - in vivo effects and relevance of histone acetylation status. Int J Radiat Oncol Biol Phys. 2009;74:546–52.PubMedCrossRef
10.
Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, et al. Histone deacetylase inhibitors radiosensitize human melanoma by suppressing DNA repair activity. Clin Cancer Res. 2005;11:4912–22.PubMedCrossRef
11.
Thiemann M, Oertel S, Ehemann V, Weichert W, Stenzinger A, Bischof M, et al. In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model. Radiat Oncol. 2012;7:52.PubMedCentralPubMedCrossRef
12.
Slingerland M, Guchelaar HJ, Gelderblom H. Histone deacetylase inhibitors: an overview of the clinical studies in solid tumors. Anticancer Drugs. 2014;25(2):140–9.PubMedCrossRef
13.
Blattmann C, Thiemann M, Stenzinger A, Christmann A, Roth E, Ehemann V, et al. Radiosensitization by Histone Deacetylase inhibition in an Osteosarcoma mouse model. Strahlenther Onkol. 2013;189(11):957–66.PubMedCrossRef
14.
Blattmann C, Oertel S, Ehemann V, Thiemann M, Huber PE, Bischof M, et al. Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys. 2010;78:237–45.PubMedCrossRef
15.
Oertel S, Thiemann M, Richter K, Weber KJ, Huber PE, Perez RL, et al. Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sacroma cell lines. Radiat Oncol. 2011;6:119.PubMedCentralPubMedCrossRef
16.
Battmann C, Thiemann T, Stenzinger A, Weichert W, Bischof M, Lopez Perez R, et al. Radiosensitization by Histone Deacetylase Inhibition in an Osteosarcoma mouse model. Strahlenther Onkol. 2013;189(11):957–66.CrossRef
17.
Bielack SS, Carrle D, Hardes J, Schuck A, Paulussen M. Bone tumors in adolescents and young adults. Curr Treat Options Oncol. 2008;9:67–80.PubMedCrossRef
18.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. 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. 2002;20:776–90.PubMedCrossRef
19.
Shabason JE, Tofilon PJ, Camphausen K. Grand rounds at the national institutes of health: HDAC inhibitors as radiation modifiers, from bench to clinic. J Cell Mol Med. 2011;15:2735.PubMedCentralPubMedCrossRef
20.
Bots M. R.W. Johnstone, Rational combinations using HDAC inhibitors. Clin. Cancer Res. 2009;15:3970–7.
21.
Jensen AD, Münter MW, Debus J. Review of clinical experience with ion beam radiotherapy. Br J Radiol. 2011;84(Spec No 1):35–47.CrossRef
22.
Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Birn. Proc Natl Acad Sci U S A. 2005;44:16090–5.CrossRef
23.
Lee CK, Wang S, Huang X, Ryder J, Liu B. HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells. Cancer Lett. 2010;296:233–40.PubMedCentralPubMedCrossRef
24.
D'Acunto CW, Fontanella B, Rodriquez M, Taddei M, Parente L, Petrella A. Histone deacetylase inhibitor FR235222 sensitizes human prostate adenocarcinoma cells to apoptosis through up-regulation of Annexin A1. Cancer Lett. 2010;295:85–91.PubMedCrossRef
25.
Frew AJ, Johnstone RW, Bolden JE. Enhancing the apoptotic and therapeutic effects of HDAC inhibitors. Cancer Lett. 2009;280:125–33.PubMedCrossRef
26.
Dickinson M, Johnstone RW. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs. 2010;28:3–20.PubMedCentralCrossRef
27.
Henderson C, Mizzau M, Paroni G, Maestro R, Schneider C, Brancolini C. Role of caspases, Bid and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). J Biol Chem. 2003;278:12579–89.PubMedCrossRef
28.
Johnstone RW, Licht JD. Histone seacetylase inhibitors in cancer therapy: Is transcription the primary target? Cancer Cell. 2003;4:13–8.PubMedCrossRef
29.
30.
Zhao Y, Lu S, Wu L, Chai G, Wang H, Chen Y, et al. Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol. 2006;26:2782–90.PubMedCentralPubMedCrossRef
31.
Kawano T, Akiyama M, Agawa-Ohta M, Mikami-Terao Y, Iwase S, Yanagisawa T, et al. Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. Int J Oncol. 2010;37:787–95.PubMed
32.
Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, et al. MK-1775, a novel wee1 kinase inhibitor radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011;17:5638–48.PubMedCentralPubMedCrossRef
33.
Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev. 2006;5:769–84.
34.
Mottet D, Castronovo V. Histone deacetylases: anti-angiogenic targets in cancer therapy. Curr Cancer Drug Targets. 2010;10(8):898–913.
Metadata
Title
Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy
Authors
Claudia Blattmann
Susanne Oertel
Markus Thiemann
Anne Dittmar
Eva Roth
Andreas E. Kulozik
Volker Ehemann
Wilko Weichert
Peter E. Huber
Albrecht Stenzinger
Jürgen Debus
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2015
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-015-0455-z

Other articles of this Issue 1/2015

Radiation Oncology 1/2015 Go to the issue

Research

Prospective longitudinal assessment of parotid gland function using dynamic quantitative pertechnate scintigraphy and estimation of dose–response relationship of parotid-sparing radiotherapy in head-neck cancers

Research

Long-term effects of neoadjuvant chemoradiotherapy followed by sphincter-preserving resection on anal sphincter function in relation to quality of life among locally advanced rectal cancer patients: a cross-sectional analysis

Research

The SMAC mimetic BV6 sensitizes colorectal cancer cells to ionizing radiation by interfering with DNA repair processes and enhancing apoptosis

Research

Which technique for radiation is most beneficial for patients with locally advanced cervical cancer? Intensity modulated proton therapy versus intensity modulated photon treatment, helical tomotherapy and volumetric arc therapy for primary radiation – an intraindividual comparison

Research

A retrospective study of the prognostic value of MRI-derived residual tumors at the end of intensity-modulated radiotherapy in 358 patients with locally-advanced nasopharyngeal carcinoma

Research

Lymph node ratio as a prognostic factor in head and neck cancer patients