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Original Article BR101801 enhances the radiosensitivity of p53-deficient colorectal cancer cells by inducing G2/M arrest, apoptosis, and senescence in a p53-independent manner

Title
Original Article BR101801 enhances the radiosensitivity of p53-deficient colorectal cancer cells by inducing G2/M arrest, apoptosis, and senescence in a p53-independent manner
Authors
Park, MijeongHa, JiminLee, YuriKwon, YoungjooChoi, Sang HyunKim, Byoung SooJeong, Youn Kyoung
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2023
Journal Title
AMERICAN JOURNAL OF CANCER RESEARCH
ISSN
2156-6976JCR Link
Citation
AMERICAN JOURNAL OF CANCER RESEARCH vol. 13, no. 12
Keywords
RadioresistanceDNA-PK inhibitorradiosensitizerp53-deficiencycolorectal cancer cellsxenograft mouse model
Publisher
E-CENTURY PUBLISHING CORP
Indexed
SCIE; SCOPUS WOS
Document Type
Article
Abstract
Inhibition of DNA-dependent protein kinase (DNA-PK) in the non-homologous end-joining repair pathway reportedly increases the radiation sensitivity of cancer cells. We have recently reported that BR101801, a novel triple inhibitor of PI3K-gamma (gamma), delta (delta), and DNA-PK, functions as an efficient sensitizer of radiation-induced DNA damage in various human solid cancer cells and a xenograft mouse model. Given that the p53 tumor suppressor gene plays an important role in radiotherapeutic efficacy, in the current study, we focused on the impact of the p53 status on BR101801-induced radiosensitization using isogenic HCT116 p53+/+ and HCT116 p53-/- human colorectal cancer cell lines. In vitro, HCT116 p53+/+ and HCT116 p53-/- human colorectal cancer cells were pretreated with 1 mu M BR101801 for 24 h before exposure to ionizing radiation (IR), followed by assays to analyze colony formation, DNA damage, cell cycle changes, senescence, autophagy, apoptosis, and DNA damage response-related proteins. Xenograft mouse models were constructed to examine the potential synergistic effects of BR101801 (50 mg/kg, orally administered once daily) and fractionated IR (2 Gy x 3 days) on tumor growth inhibition in vivo. BR101801 inhibited cell proliferation and prolonged DNA damage in both HCT116 p53+/+ and HCT116 p53-/- human colorectal cancer cells. Combined treatment with BR101801 and IR robustly induced G2/M phase cell cycle arrest, apoptosis, and cellular senescence in HCT116 p53-/- cells when compared with treatment with IR alone. Furthermore, BR101801 synergistically inhibited tumor growth in the HCT116 p53-/- xenograft mouse model. BR101801 enhanced the radiosensitivity of HCT116 human colorectal cancer cells regardless of their p53 status. Moreover, BR101801 exerted robust synergistic effects on IR-induced cell cycle arrest, apoptosis, and tumor growth inhibition, even in radioresistant HCT116 p53-/- cells. Overall, these findings provide a scientific rationale for combining BR101801 with IR as a new therapeutic strategy to overcome radioresistance induced by p53 deficiency.
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약학대학 > 약학과 > Journal papers
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