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Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model
C Blattmann1, M Thiemann, A Stenzinger
1Pädiatrie 5, Olgahospital, Bismarckstr. 8, 70176, Stuttgart, Germany, c.blattmann@klinikum-stuttgart.de.
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.
Insights
Combining suberoylanilide hydroxamic acid (SAHA) with radiotherapy (XRT) enhances osteosarcoma (OS) radiosensitivity. This dual therapy significantly inhibits tumor growth by increasing apoptosis and reducing proliferation.
Area of Science:
- Oncology
- Cancer Research
- Radiotherapy
Background:
- Osteosarcomas (OS) are aggressive, radioresistant bone cancers.
- Histone deacetylase inhibitors (HDACi) are a promising class of anticancer drugs.
Purpose of the Study:
- To evaluate the combined efficacy of SAHA and radiotherapy in treating OS.
- To investigate the underlying mechanisms of this combined treatment.
Main Methods:
- Assessed clonogenic survival and tumor growth delay in OS cell lines and xenografts.
- Monitored proliferation, necrosis, angiogenesis, and apoptosis via immunohistochemistry.
- Analyzed the CD95 pathway, caspase activity, and CD95 signaling inhibition.
Main Results:
- Combined SAHA and XRT significantly reduced OS cell survival and tumor growth compared to XRT alone.
- Dual therapy increased apoptosis and decreased proliferation and angiogenesis.
- Treatment elevated p53, p21, CD95, and CD95L expression; CD95 inhibition reduced apoptosis.
Conclusions:
- HDACi enhances osteosarcoma radiosensitivity, partly through ligand-induced apoptosis.
- HDACi represents a potential therapeutic component for osteosarcoma treatment.
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