期刊
AMERICAN JOURNAL OF CANCER RESEARCH
卷 11, 期 11, 页码 5440-+出版社
E-CENTURY PUBLISHING CORP
关键词
DNA-PK inhibitor; Ionizing radiation; radiosensitizer; DNA damage repair; solid cancer
类别
资金
- Korea Institute of Radiological and Medical Sciences (KIRAMS) [51322-2019, 51323-2019]
- Boryung Pharmaceutical [BR101801]
The study showed that BR101801, a DNA-PK inhibitor, can effectively enhance genomic instability induced by ionizing radiation and increase sensitivity in human solid cancer cells through multiple pathways. It affects factors in both the non-homologous end-joining repair pathway and homologous recombination.
DNA-dependent protein kinase (DNA-PK), an essential component of the non-homologous end-joining (NHEJ) repair pathway, plays an important role in DNA damage repair (DDR). Therefore, DNA-PK inhibition is a promising approach for overcoming radiotherapy or chemotherapy resistance in cancers. In this study, we demonstrated that BR101801, a potent DNA-PK inhibitor, acted as an effective radiosensitizer in various human solid cancer cells and an in vivo xenograft model. Overall, BR101801 strongly elevated ionizing radiation (IR)-induced genomic instability via induction of cell cycle G2/M arrest, autophagic cell death, and impairment of DDR pathway in human solid cancer cells. Interestingly, BR101801 inhibited not only phosphorylation of DNA-PK catalytic subunit in NHEJ factors but also BRCA2 protein level in homologous recombination (HR) factors. In addition, combination BR101801 and IR suppressed tumor growth compared with IR alone by reducing phosphorylation of DNA-PK in human solid cancer xenografts. Our findings suggested that BR101801 is a selective DNA-PK inhibitor with a synergistic radiosensitizing effect in human solid cancers, providing evidence for clinical applications.
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