Abstract
Aim
In osteosarcoma, local control of the tumour is absolutely critical otherwise the chances of long term survival are <10% and may effectively approach zero. Radiotherapy is used in case of non-resectable tumours. Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation (XRT) by altering numerous molecular pathways. Therefore, we investigated the effect of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on radiation response in osteosarcoma (OS) and rhabdomyosarcoma (RMS) cell lines.
Methods
Clonogenic survival, cell cycle analysis, apoptosis and gammaH2AX phosphorylation as a marker of DNA double strand breaks (DSBs) were examined in two OS (KHOS-24OS, SAOS2) and two RMS (A-204, RD) cell lines treated with SAHA alone and SAHA plus XRT, respectively. Protein expression was investigated via immunoblot analysis, cell cycle analysis, measurement of apoptosis and gammaH2AX expression were performed using flow cytometry.
Results
In the sarcoma cell lines, SAHA induced an inhibition of cell proliferation and clonogenic survival and lead to a significant radiosensitization. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In both tumour entities, gammaH2AX expression was significantly increased when XRT was combined with SAHA treatment which was correlated with attenuation of radiation-induced DNA repair protein expression.
Conclusion
Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair rather than increased apoptosis induction after exposure to HDACIs could be one key mechanism of radiosensitization by HDACIs.
