AZD7648, a DNA-PKcs inhibitor, overcomes radioresistance in Hep3B xenografts and cells under tumor hypoxia
- 주제(키워드) AZD7648 , cancer , HIF-1 alpha , hypoxia , ionizing radiation , radioresistance , radiosensitizer , xenograft mouse
- 주제(기타) Oncology
- 설명문(일반) [Ha, Jimin; Park, Mijeong; Lee, Yuri; Jeong, Youn Kyoung] Korea Inst Radiol & Med Sci KIRAMS, Radiol & Med Support Ctr, Seoul 01812, South Korea; [Ha, Jimin; Lee, Yuri; Ha, Hunjoo] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul, South Korea; [Choi, Sang Hyun] Korea Inst Radiol & Med Sci, Res Team Radiol Phys & Engn, Seoul, South Korea; [Kim, Byoung Soo] Korea Inst Radiol & Med Sci, Div Appl RI, Seoul, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 E-CENTURY PUBLISHING CORP
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000213442
- 본문언어 영어
- PubMed 37970336
초록/요약
Radiation therapy is one of the most commonly used cancer treatments. However, it has important concerns such as damage to normal tissues around cancers and radioresistance. To overcome these problems, combination therapy using radiosensitizer and radiotherapy will be a good alternative. The present study investigated the effects of AZD7648 on overcoming radioresistance as well as radiosensitizing in Hep3B xenografts and cells. The results showed that AZD7648 enhanced ionizing radiation (IR)-induced tumor growth not only in radiosensitive but also radioresistant tumors. In particular, the combination of AZD7648 with radiation reduced the expression of hypoxia induce factor-1 alpha (HIF-1 alpha) in radioresistant tumors. In vitro studies, AZD7648 plus IR increased IR-induced G2/M arrest and regulated cell cycle checkpoints such as cyclinB1, p-cdc2 in normoxia but not in hypoxia. AZD7648 induced more radiation-mediated ROS than radiation only under normoxia, but these ROS were not altered by AZD7648 under hypoxia. Interestingly, AZD7648 downregulated HIF-1 alpha expression level under CoCl2-treated hypoxic condition but not in normoxic condition. In conclusion, AZD7648 synergistically increased radiosensitivity through accumulating IR-induced G2/M arrest and further improved radioresistance via regulation of HIF-1 alpha. The present data suggest that AZD7648 may be a strong radiosensitizer in radioresistant as well as radiosensitive cancers.
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