S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Radiosensitization by a novel DNMT Inhibitor, MA 17 and its mechanism in vitro
새로운 DNMT 저해제, MA 17의 방사선 감작 메커니즘에 관한 연구
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의학과, 2018. 2. 김일한.
- Introduction: Epigenetic alteration is known to be an important gene regulatory mechanism. Because the regulation of DNA methyltransferase (DNMT) has been implicated in the regulation of cellular response to radiation, DNMT inhibitors might be considered potential targets for radio-sensitization. We report the evaluation of the in vitro radio-sensitizing activities of a novel DNMT inhibitor termed MA-17.
Methods and Materials: A549 (lung cancer) cells were exposed to radiation with or without MA-17. Cell survival curves were obtained via clonogenic assays. We investigated the pathways and the relevant gene ontology associated with any of the identified differentially expressed genes (DEGs) to seek the underlying mechanism of MA-17 for radio-sensitization. Cell cycle and apoptosis were analyzed via flow cytometry. Expression of γH2AX, a marker of radiation-induced DNA double-strand break (DSB), was examined by immunocytochemistry.
Results: Pretreatment with MA-17 radio-sensitized A549 cells at an IC50 of 120uM, where the sensitization enhancement ratio was 1.73 for a survival fraction of 0.5. MA-17 down-regulated DNA homologous recombination and the Fanconi anemia pathway in according to transcriptome analysis, and increased expressions of several genes relevant to the apoptosis pathway were observed. An increased the sub-G1 fraction and prolongation of γH2AX expression of A549 cells were observed in the cells treated with MA-17 prior to radiation as compared with those treated by radiation alone.
Conclusions: MA-17 is the novel DNMT inhibitor, enhanced radio-sensitivity in A549 cells, which is associated with inhibition of repair of DNA DSB and enhanced apoptosis.