방사선생물학

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  • [J Pharmacol Exp Ther.] Radiosensitizing effect of novel phenylpyrimidine derivatives on human lung cancer cells via cell cycle perturbation.신규 phenylpyrimidine유도체의 방사선민감화 연구

    KIRAMS / 정승윤, 송지영*

  • 출처
    J Pharmacol Exp Ther.
  • 등재일
    2019 Jun 28. pii: jpet.119.257717. doi: 10.1124/jp
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    Abstract
    Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound; 17 derivatives of this lead compound were examined in the present study. PPA5, 13, 14, 15, and 17 inhibited cell viability by more than 50% with a marked increase in the proportion of cells arrested at the G2/M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinases 1 (CDK1). Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT: Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers.

     


    Author information

    Jung SY1, Nam KY2, Park JI1, Song KH1, Ahn J1, Park JK1, Um HD1, Hwang SG1, Choi SU3, Song JY4.
    1
    Korea Institute of Radiological & Medical Sciences.
    2
    Pharos I&BT Co., Ltd.,.
    3
    Korea research Institute of Chemical Technology.
    4
    Korea Institute of Radiological & Medical Sciences; immu@kirams.re.kr.

     

  • 키워드
    anticancer agents; cancer chemotherapy; cell cycle; drug discovery; radiation; resistance; tyrosine kinases
  • 편집위원

    방사선치료 과정에서의 저항성은 치료효율 저하의 가장 큰 원인이 되므로, 방사선민감제의 개발은 매우 중요한 이슈가 된다. 본 연구에서는 p53과 Nrf2를 표적으로 하는 high-throughput screening을 통해 발굴한 phenylpyrimidine derivatives가 cell cycle의 조절인자인 CDK를 억제함으로써 폐암 방사선 치료의 민감제로 활용할 수 있음을 규명하였다.

    2019-07-18 15:27:39

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