Radiosensitization of Glioblastoma Cells by a Novel DNA Methyltransferase-inhibiting Phthalimido-Alkanamide Derivative.

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.

• Authors: Chan Woo Wee, Jin Ho Kim, Hak Jae Kim, Hyun-Cheol Kang, Soo Youn Suh, Beom Soo Shin, Eunsook Ma, Il Han Kim
• Journal: Anticancer research (Anticancer Res) Vol. 39 Issue 2 Pg. 759-769 (Feb 2019) ISSN: 1791-7530 [Electronic] Greece
• PMID: 30711955 (Publication Type: Journal Article)
• Copyright: Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Alkanes
• FANCA protein, human
• Fanconi Anemia Complementation Group A Protein
• Phthalimides
• Radiation-Sensitizing Agents
• phthalimido-alkanamide MA17
• DNA (Cytosine-5-)-Methyltransferase 1
• DNMT1 protein, human

Topics

• Alkanes (pharmacology)
• Animals
• Apoptosis
• Astrocytes (drug effects, radiation effects)
• Autophagy
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA (Cytosine-5-)-Methyltransferase 1 (antagonists & inhibitors)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Repair
• Fanconi Anemia Complementation Group A Protein (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, radiotherapy)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Phthalimides (pharmacology, therapeutic use)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)