Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Enhancement of Sensitivity of Human Lung Cancer Cell Line to TRAIL and Gefitinib by IGF-1R Blockade

폐암세포주에서 IGF-1R 억제를 이용한 TRAIL 및 gefitinib에 대한 감수성 증가를 위한 연구

  • Lee, Yoon-Jin (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Park, Mi-Young (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Kang, Young-Ae (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Kwon, Sung-Youn (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Yoon, Ho-Il (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Lee, Jae-Ho (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital) ;
  • Lee, Choon-Taek (Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital)
  • 이윤진 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 박미영 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 강영애 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 권성연 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 윤호일 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 이재호 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터) ;
  • 이춘택 (서울대학교 의과대학 내과, 의학연구원 폐연구소, 분당서울대학교병원 내과, 폐센터)
  • Received : 2007.04.20
  • Accepted : 2007.07.09
  • Published : 2007.07.30
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Abstract

Background: TRAIL is a cytokine that selectively induces apoptosis in various cancer cell lines. Gefitinib is new targeted drug applied in lung cancer that selectively inhibits EGFR tyrosine kinase. However, lung cancers have shown an initial or acquired resistance to these drugs. This study examined the effect of IGF-1R and its blockade on enhancing the sensitivity of lung cancer cell lines to TRAIL and gefitinib. Methods: Two lung cancer cell lines were used in this study. NCI H460 is very sensitive to TRAIL and gefitinib. On the other hand, A549 shows moderate resistance to TRAIL and gefitinib. The IGF-1R blockade was performed using adenoviruses expressing the dominant negative IGF-1R and shRNA to IGF-1R and AG1024 (IGF-1R tyrosine kinase inhibitor). Results: The adenovirus expressing dominant negative IGF-1R(950st) induced the increased expression of defective IGF-1R on the lung cancer cell surface, and the adenovirus-shIGF-1R effectively decreased the level of IGF-1R expression on cell surface. The genetic blockade of IGF-1R by the adenovirus-dnIGF-1R and AG1024 increased the sensitivity of A549 cells to TRAIL. The reduction of IGF-1R by transduction with ad-shIGF-1R also increased the sensitivity of the A549 cells to gefitinib. Conclusion: The blockade of IGF-1R through various mechanisms increased the sensitivity of the lung cancer cell line that was resistant to TRAIL and gefitinib. However, further studies using other cell lines showing acquired resistance as well as in vivo animal experiments will be needed.

배 경: 폐암의 새로운 치료제로 각광을 받고 있는 TRAIL은 암에 선택적으로 apoptosis를 일으킨다고 알려진 cytokine으로 알려져 있다. 또한 gefitinib (Iressa)는 폐암의 적용된 최초의표적치료제로 각광을 받고 있다. 그러나 일부의 암세포에서는 이에 대한 저항성을 보이고 있다. 본 연구에서는 암세포에서 외부의 apoptotic 자극에 저항성을 보이는 IGF-1R를 억제함으로 TRAIL 및 gefitinib의 항암작용을 증가시키고자 실험을 시행하였다. 방 법: 암세포주는 TRAIL 및 gefitinib에 민감한 NCI H460와 두 약제에 중등도의 저항성을 보이는 A549의 폐암세포주로 시행하였으며 IGF-1R의 억제는 본 연구자가 개발하였던 IGF-1 pathway를 dominant negative inhibition을 할 수 있는 adenovirus- IGF1R(482 ST, 950ST) 및 IGF-1R tyrosine kinase inhibitor인 Tyrphostin AG1024를 사용하였고 gefitinib에 대한 실험에서는 RNA interference를 이용하여 IGF-1R의 발현을 억제하는 adenovirus- shIGF-1R을 이용하였다. 결 과: TRAIL에 저항성을 보이는 폐암세포주(A549)에서 adenovirus-IGF1R(482ST, 950ST) 및 AG1024로 IGF-1R를 억제한 후 TRAIL을 투여한 경우 항암효과가 증대되었다. A549에 adenovirus- shIGF-1R을 감염시켜 IGF-1R의 발현을 억제한 결과 gefitinib에 대한 감수성이 증가되었다.

Keywords

References

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