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Abstract
BACKGROUND/AIM:
Strategies to enhance the therapeutic ratio of radiotherapy in glioblastoma are warranted. Our aim was to report a novel DNA methyltransferase inhibitor as a potential radiosensitizing agent in glioblastoma.

MATERIALS AND METHODS:
Four glioblastoma cell lines and one normal astrocyte cell line were incubated with a newly-synthetized phthalimido-alkanamide derivative, MA17, and its radiosensitizing effects were assessed. We performed a tumor growth delay assay in two glioblastoma lines: U87MG and U138MG. We evaluated DNA methyltransferase (DNMT) inhibition, apoptosis, autophagy, DNA damage repair, and FANCA expression.

RESULTS:
MA17 radiosensitized all glioblastoma cells (all p<0.05), but it did not affect normal astrocytes (p=0.193). MA17 significantly prolonged the mean tumor doubling time in vivo, in cells treated in addition with radiotherapy, compared to radiotherapy alone (p<0.05). DNMT activity was down-regulated, and apoptosis and autophagy were induced by MA17. Double-stranded DNA break foci were observed for prolonged periods in cells treated with MA17. FANCA expression was also inhibited.

CONCLUSION:
A novel phthalimido-alkanamide derivative demonstrated significant radiosensitization in glioblastoma cells in vitro and in vivo. Further investigation is needed to translate these results to the clinic.

Author information

Wee CW1, Kim JH1,2,3, Kim HJ1,2,3, Kang HC1, Suh SY2, Shin BS4, Ma E5, Kim IH6,2,3.
1
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
3
Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
4
School of Pharmacy, Sungkyunkwan University, Seoul, Republic of Korea.
5
College of Pharmacy, Catholic University of Daegu, Gyeongsan, Republic of Korea ihkim@snu.ac.kr masook@cu.ac.kr.
6
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea ihkim@snu.ac.kr masook@cu.ac.kr.