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 1/2011

Open Access 01-12-2011 | Research

Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines

Authors: Susanne Oertel, Markus Thiemann, Karsten Richter, Klaus-J Weber, Peter E Huber, Ramon Lopez Perez, Stephan Brons, Marc Bischof, Andreas E Kulozik, Volker Ehemann, Jürgen Debus, Claudia Blattmann

Published in: Radiation Oncology | Issue 1/2011

Login to get access

Abstract

Introduction

The pan-HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) has previously shown to be a radio-sensitizer to conventional photon radiotherapy (XRT) in pediatric sarcoma cell lines. Here, we investigate its effect on the response of two sarcoma cell lines and a normal tissue cell line to heavy ion irradiation (HIT).

Materials and methods

Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring γH2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and γH2AX.

Results

Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines - again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA.

Conclusion

Our in vitro data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines.
Appendix
Available only for authorised users
Literature
1.
Minucci S, Pelicci P: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006, 6: 38-51. 10.1038/nrc1779CrossRefPubMed
2.
Wilson AJ, Chueh AC, Tögel L, et al.: Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction. Cancer Res 2010,70(2):609-620. 10.1158/0008-5472.CAN-09-2327PubMedCentralCrossRefPubMed
3.
Furchert SE, Lanvers-Kaminsky C, Jürgens H, et al.: Inhibitor of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer 2007, 120: 1787-1794. 10.1002/ijc.22401CrossRefPubMed
4.
Lee M-J, Kim YS, Kummar S, et al.: Histone deacetylase inhibitors in cancer therapy. Curr Opin Oncol 2008, 20: 639-649. 10.1097/CCO.0b013e3283127095CrossRefPubMed
5.
Dalgard CL, Van Quil KR, O'Brien JM, et al.: Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma. Clin Cancer Res 2008,14(10):3113-3123. 10.1158/1078-0432.CCR-07-4836CrossRefPubMed
6.
Yang C, Choy E, Hornicek FJ, et al.: Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells. Cancer Chemother Pharmacol 2011,67(2):439-46. 10.1007/s00280-010-1344-7CrossRefPubMed
7.
Blattmann C, Oertel S, Ehemann V, et al.: Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 2010,78(1):237-245. 10.1016/j.ijrobp.2010.03.010CrossRefPubMed
8.
Camphausen K, Tofilon PJ: Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol 2007, 25: 4051-4056. 10.1200/JCO.2007.11.6202CrossRefPubMed
9.
Karagiannis TC, El Osta A: Modulation of cellular radiation response by histone deacetylase inhibitors. Oncogene 2006, 25: 3885-3893. 10.1038/sj.onc.1209417CrossRefPubMed
10.
Munshi A, Tanaka T, Hobbs ML, et al.: Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 2006, 5: 1967-74. 10.1158/1535-7163.MCT-06-0022CrossRefPubMed
11.
12.
Hada M, Sutherland BM: Spectrum of complex DNA damages depends on the incident radiation. Radiat Res 2006,165(2):223-30. 10.1667/RR3498.1CrossRefPubMed
13.
Blattmann C, Oertel S, Schulz-Ertner D, et al.: Non-randomized therapy trial to determine the safety and efficacy of heavy ion radiotherapy in patients with non-resectable osteosarcoma. BMC Cancer 2010, 10: 96. 10.1186/1471-2407-10-96PubMedCentralCrossRefPubMed
14.
Kano M, Yamada S, Hoshino I, et al.: Effects of carbon-ion radiotherapy combined with a novel histone deacetylase inhibitor, cyclic hydroxamic-acid-containing peptide 31 in human esophageal squamous cell carcinoma. Anticancer Res 2009,29(11):4433-8.PubMed
15.
Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 1979, 5: 85-91.CrossRefPubMed
16.
O'Connor OA, Heaney ML, Schwartz L, et al.: Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006, 24: 166-73. 10.1200/JCO.2005.01.9679CrossRefPubMed
17.
Baschnagel A, Russo A, Burgan WE, et al.: Vorinostat enhances the radiosensitivity of a breast cancer brain metastatic cell line grown in vitro and as intracranial xenografts. Mol Cancer Ther 2009,8(6):1589-95. 10.1158/1535-7163.MCT-09-0038PubMedCentralCrossRefPubMed
18.
Vasirredy RS, Shung CN, Cempaka NL, et al.: H2AX phosphorylation screens from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype. Br J Cancer 2010,102(10):1511-1518. 10.1038/sj.bjc.6605666CrossRef
19.
Chung YL, Lee MY, Pui NN: Epigenetic therapy using the histone deacetylase inhibitor for increasing therapeutic gain in oral cancer: prevention of radiation-induced oral mucositis and inhibition of chemical-induced oral carcinogenesis. Carcinogenesis 2009,30(8):1387-1397. 10.1093/carcin/bgp079CrossRefPubMed
20.
Chinnaiyan P, Vallabhaneni G, Armstrong E, et al.: Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 2005, 62: 223-9. 10.1016/j.ijrobp.2004.12.088CrossRefPubMed
21.
Camphausen K, Burgan W, Cerra M, et al.: Enhanced radiation-induced cell killing and prolongation of χH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res 2004, 64: 316-21. 10.1158/0008-5472.CAN-03-2630CrossRefPubMed
22.
Storch K, Eke I, Borgmann K, et al.: Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Res 2010, 70: 3925-34. 10.1158/0008-5472.CAN-09-3848CrossRefPubMed
23.
Oishi T, et al.: Proliferation and cell death of human glioblastoma cells after carbon-ion beam exposure: morphologic and morphometric analyses. Neuropathology 2008, 28: 408-416. 10.1111/j.1440-1789.2008.00899.xCrossRefPubMed
24.
Hamada N, Tatsuhiko I, Masunaga S, et al.: Recent advances in the Biology of heavy-ion cancer therapy. J Radiat Res 2010, 51: 365-83. 10.1269/jrr.09137CrossRefPubMed
25.
Pawlik TM, Keyomarsi K: Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 2004,59(4):928-42. 10.1016/j.ijrobp.2004.03.005CrossRefPubMed
26.
Hollstein M, et al.: p53 mutations in human cancers. Science 2001, 253: 49-53.CrossRef
27.
28.
Takahashi T, Fukawa T, Hirayama R, et al.: In vitro interaction of high-LET heavy-ion irradiation and chemotherapeutic agents in two cell lines with different radiosensitivities and different p53 status. Anticancer Res 2010,30(6):1961-7.PubMed
29.
Singh TR, Shankar S, Srivastava RK: HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 2005, 24: 4609-23. 10.1038/sj.onc.1208585CrossRefPubMed
30.
Takahashi A, Matsumoto H, Furusawa Y, et al.: Apoptosis induced by high-LET radiations is not affected by cellular p53 gene status. Int J Radiat Biol 2005, 81: 581-6. 10.1080/09553000500280484CrossRefPubMed
31.
Blakely EA, Chang PY: Biology of charged particles. Cancer J 2009, 15: 271-84. 10.1097/PPO.0b013e3181b666c5CrossRefPubMed
32.
Huo JX, Metz SA, Li GD: p53-independent induction of p21(waf1/cip1) contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells. Cell Death Differ 2004,11(1):99-109. 10.1038/sj.cdd.4401322CrossRefPubMed
33.
Banath J, MacPhail S, Olive P: Radiation Sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell cines. Cancer Res 2004, 64: 7144-9. 10.1158/0008-5472.CAN-04-1433CrossRefPubMed
34.
Mills J, Hricik T, Siddiqi S, et al.: Chromatin structure predicts epigenetic therapy responsiveness in sarcoma. Mol Cancer Ther 2011, (10):313-323.
Metadata
Title
Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines
Authors
Susanne Oertel
Markus Thiemann
Karsten Richter
Klaus-J Weber
Peter E Huber
Ramon Lopez Perez
Stephan Brons
Marc Bischof
Andreas E Kulozik
Volker Ehemann
Jürgen Debus
Claudia Blattmann
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2011
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/1748-717X-6-119

Other articles of this Issue 1/2011

Radiation Oncology 1/2011 Go to the issue

Research

Technology assessment of automated atlas based segmentation in prostate bed contouring

Research

Rotational IMRT techniques compared to fixed gantry IMRT and Tomotherapy: multi-institutional planning study for head-and-neck cases

Case report

Successful radiopeptide targeting of metastatic anaplastic meningioma: Case report

Research

Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series

Research

A 4D IMRT planning method using deformable image registration to improve normal tissue sparing with contemporary delivery techniques

Research

Registration accuracy for MR images of the prostate using a subvolume based registration protocol