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Abstract
The targeting of DNA methylation in cancer using DNA hypomethylating drugs has been well known to sensitize cancer cells to chemotherapy and immunotherapy by affecting multiple pathways. Herein, we investigated the combinational effects of DNA hypomethylating drugs and ionizing radiation (IR) in human sarcoma cell lines both in vitro and in vivo. Clonogenic assays were performed to determine the radiosensitizing properties of two DNA hypomethylating drugs on sarcoma cell lines we tested in this study with multiple doses of IR. We analyzed the effects of 5-aza-dC or SGI-110, as DNA hypomethylating drugs, in combination with IR in vitro on the proliferation, apoptosis, caspase-3/7 activity, migration/invasion, and Western blotting using apoptosis- or autophagy-related factors. To confirm the combined effect of DNA hypomethylating drugs and IR in our in vitro experiment, we generated the sarcoma cells in nude mouse xenograft models. Here, we found that the combination of DNA hypomethylating drugs and IR improved anticancer effects by inhibiting cell proliferation and by promoting synergistic cell death that is associated with both apoptosis and autophagy in vitro and in vivo. Our data demonstrated that the combination effects of DNA hypomethylating drugs with radiation exhibited greater cellular effects than the use of a single agent treatment, thus suggesting that the combination of DNA hypomethylating drugs and radiation may become a new radiotherapy to improve therapeutic efficacy for cancer treatment.

Affiliations

Moon-Taek Park  1 , Sung-Dae Kim  1 , Yu Kyeong Han  2 , Jin Won Hyun  3 , Hae-June Lee  4 , Joo Mi Yi  2
1 Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, Republic of Korea.
2 Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea.
3 Jeju National University School of Medicine and Jeju Research Center for Natural Medicine, Jeju 63243, Republic of Korea.
4 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.