Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
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Leptomycin B Increases Radiosensitization by Trichostain A in HeLa Cells

HeLa세포주에서 Leptomicin B에 의한 Trichostain A의 방사선 감작효과의 증가

  • Kim, In-An (Department of Radiation Oncology, Cancer Research institute, Seoul National University College of Medicine, Department of Radiation Oncology, Seoul National University Bundang Hospital) ;
  • Kim, Jin-Ho (Department of Radiation Oncology, Cancer Research Institute, Seoul National University College of Medicine) ;
  • Shin, Jin-Hee (Department of Radiation Oncology, Cancer Research Institute, Seoul National University College of Medicine) ;
  • Kim, Il-Han (Department of Radiation Oncology, Cancer Research Institute, Institute of Radiation medicine, Seoul National University College of Medicine) ;
  • Kim, Jae-Sung (Department of Radiation Oncology, Cancer Research Institute, Department of Radiation Oncology, Seoul National University Bundang Hospital) ;
  • Wu-Hong, Gyun (Department of Radiation Oncology, Cancer Research Institute, Institute of Radiation medicine, Seoul National University College of Medicine) ;
  • Chie, Eui-Kyu (Department of Radiation Oncology, Cancer Research Institute, Seoul National University College of Medicine) ;
  • Kim, Yong-Ho (Department of Radiation Oncology, Seoul National University College of Medicine, Department of Radiation Oncology, Soonchunhyang University Hospital) ;
  • Kim, Bo-Kyung (Department of Radiation Oncology, Seoul National University College of Medicine, Department of Radiation Oncology, Dankook University Hospital) ;
  • Hong, Se-Mie (Department of Radiation Oncology, Seoul National University College of Medicine, Department of Radiation Oncology, Konkuk University Hospital) ;
  • Ha, Sung-Whan (Department of Radiation Oncology, Institute of Radiation Medicine, Seoul National University College of Medicine) ;
  • Park, Chan-Il (Department of Radiation Oncology, Institute of Radiation Medicine, Seoul National University College of Medicine)
  • 김인아 (서울대학교 의과대학 방사선종양학교실, 암연구소, 분당서울대학병원 방사선종양학과) ;
  • 김진호 (서울대학교 의과대학 방사선종양학교실, 암연구소) ;
  • 신진희 (서울대학교 의과대학 방사선종양학교실, 암연구소) ;
  • 김일한 (서울대학교 의과대학 방사선종양학교실, 암연구소, 의학연구원 방사선의학연구소) ;
  • 김재성 (서울대학교 의과대학 방사선종양학교실, 암연구소, 분당서울대학병원 방사선종양학과) ;
  • 우홍균 (서울대학교 의과대학 방사선종양학교실, 암연구소, 의학연구원 방사선의학연구소) ;
  • 지의규 (서울대학교 의과대학 방사선종양학교실, 암연구소) ;
  • 김용호 (서울대학교 의과대학 방사선종양학교실, 순천향대학교병원 방사선종양학과) ;
  • 김보경 (서울대학교 의과대학 방사선종양학교실, 단국대학교병원 방사선종양학과) ;
  • 홍세미 (서울대학교 의과대학 방사선종양학교실, 건국대학교병원 방사선종양학과) ;
  • 하성환 (서울대학교 의과대학 방사선종양학교실, 의학연구원 방사선의학연구소) ;
  • 박찬일 (서울대학교 의과대학 방사선종양학교실, 의학연구원 방사선의학연구소)
  • Published : 2005.06.01
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Abstract

Purpose: Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components of anticancer therapy and their radiosensitizing effects have become evident. Specific HDAS are now available that preferentially inhibit specific HDAC classes; TSA inhibits Class I and II HDACs, and SK7041 inhibits Class I HDACs. Materials and methods: We tested the differential radiosensitization induced by two different classes of HDIs in HeLa cells. We next tested the hypothesis that p53 expression in cancer cells may influence the susceptibility to HDIs by using pharmacologic modification of the p53 status under an isogenic background. Results: It is interesting that p53 expression in the HeLa cells clearly increased the degree of radio-sensitization by TSA compared to that of the class I specific inhibitor SK7041. This suggests that p53 may, in part, be responsible for the mechanistic role for the greater radiosensitization induced by Class I & II inhibitors compared to that of the class I specific inhibitors. Thus, these studies are useful in distinguishing between events mediated solely by the Class I HDACS versus those events involving the other classes of HDACS as well. Conclusion: The anticancer efficacy of targeting Class I and II HDACS, in conjunction with radiation therapy, may be further enhanced by the restoration of p53 expression.

목적: 히스톤탈아세틸화효소 억제제는 그 자체의 항암효과뿐만 아니라 방사선 감작제로서의 효과가 점차분명해져가고 있다. 최근 Class I 특이적인 히스톤탈아세틸화효소 억제제의 개발로 계층 특이적인(Class specific) 연구가 가능해짐에 따라, 본 연구에서는 서로 다른 히스톤탈아세틸화효소억제제의 방사선감작효과를 비교함과 동시에 p53 발현도의 차이가 히스톤탈아세틸화효소억제제의 방사선 감수성에 미치는 영향을 알아보고자 하였다. 대상 및 방법: 이를 위해 p53 발현도가 매우 낮은 HeLa 세포에 p53의 핵 외 수송을 억제하여 세포질 내 분해를 차단하는 Leptomycin B를 처리하여 p53의 발현도를 현저하게 높인 후, Trichostatin와 SK7041의 방사선 민감도를 비교 관찰하였다. 결과: 세포생존곡선, SER 및 SF2를 비교 분석 시, p53의 발현이 높은 Leptomycin B 처리군에서 Trichostatin A가 Class I HDAC만을 억제하는 SK7041에 비해 유의하게 높은 방사선 감작효과를 나타내었다. 이는 p53이 Class I 특이적 억제제인 SK7041과 Class I과 II를 모두 억제하는 TSA의 방사선감작효과에 미치는 영향의 차이에 기전적으로 관여함을 시사한다. 결론: Leptomycln B에 의해 유도된 p53의 발현증가는 Class I과 Class I과 II를 모두 억제하는 TSA의 방사선 감작효과를 증강시킨다.

Keywords

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