Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Anti-tumor effect of new compound, 127, through the induction of apoptosis

새로운 화합물 c-127의 세포고사 유도에 의한 항암효과

  • Baek, Ki Hwan (Department of Pediatrics, Wonkwang University School of Medicine) ;
  • Han, A Lum (Department of Family Medicine, Wonkwang University School of Medicine) ;
  • Shin, Sae Ron (Department of Family Medicine, Wonkwang University School of Medicine) ;
  • Jin, Chun Mae (Zoonosis Research Center, Wonkwang University School of Medicine) ;
  • Yoon, Young Wook (Department of Pediatrics, Wonkwang University School of Medicine) ;
  • Yu, Seung Taek (Department of Pediatrics, Wonkwang University School of Medicine) ;
  • Kim, Jong Duk (Department of Pediatrics, Wonkwang University School of Medicine) ;
  • Choi, Du Young (Department of Pediatrics, Wonkwang University School of Medicine)
  • 백기환 (원광대학교 의과대학 소아과학교실) ;
  • 한아름 (원광대학교 의과대학 가정의학과교실) ;
  • 신새론 (원광대학교 의과대학 가정의학과교실) ;
  • 진춘매 (원광대학교 의과대학 인수공통감염병 연구센터) ;
  • 윤영욱 (원광대학교 의과대학 소아과학교실) ;
  • 유승택 (원광대학교 의과대학 소아과학교실) ;
  • 김종덕 (원광대학교 의과대학 소아과학교실) ;
  • 최두영 (원광대학교 의과대학 소아과학교실)
  • Received : 2008.12.05
  • Accepted : 2009.05.08
  • Published : 2009.06.15
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Abstract

Purpose : We screened more than 350 compounds with an endoperoxide ring structure in search of an anti-leukemic drug and found that compound 127 (c-127) could induce significant cytotoxicity in HL-60 cells. In this study, we investigated the molecular mechanisms of compound 127-induced antitumor activity on HL-60 cells. Methods : HL-60 cells were cultured in Rosewell Park Memorial Institute 1640 and cell viability was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], a tetrazole assay. Apoptosis was assessed by a DNA fragmentation test. Apoptotic machineries were determined by Western blot analysis. Results : C-127 could induce a cytotoxic effect at 24 h and apoptosis at 6 h, which was demonstrated with MTT assay and DNA fragmentation test, respectively. The apoptotic effect of this drug was caused by the activation of the intracellular caspase-8,3 activation, the cleavage of pro-apoptotic Bid, and the increase of c-Jun expression accompanied with JNK (Jun N-terminal kinases) phosphorylation. On the contrary, it increased the expression of anti-apoptotic Bcl-2 levels, leading to the induction of the induction of anti-apoptotic effect. Taken together, the present study demonstrated that c-127 was a potent inducer of cytotoxicity on HL-60 cells through apoptotic mechanisms, which included the activation of caspase family, the regulation of Bcl-2 family, and the activation of JNK signaling pathway. Conclusion : Our results suggest that c-127 has a strong antitumor activity through the regulation of various apoptotic machineries on HL-60 cells. The compound may be utilized as an effective and potentially therapeutic drug in leukemia.

목 적 : Artemisinin은 인체에 대한 부작용이 적고 항말라리아 효능 뿐 아니라 강력한 항암효과가 있음이 알려져 있다. 저자들은 오까야마 약학대학에서 합성 된 350여개의 endoperoxide ring구조를 가진 artemisinin 유도체를 선별검사 하여 HL-60세포 주에 강력한 세포독성을 보여 준 c-127의 세포고사 유도 여부와 그 분자유전학적 기전을 알아보고자 하였다. 방 법 : HL-60세포는 RPMI 1640배지로 배양하였고 세포 생존율은 MTT분석으로 측정하였다. 세포고사 여부는 DNA추출과 전기영동법으로 확인하였으며 세포고사 유도 기전은 western blotting을 시행하여 알아보았다. 결 과 : C-127이 세포고사를 유도하여 HL-60세포의 세포 생존력을 농도 의존적으로 감소시켰다. C-127의 이런 항암효과의 분자 유전학적 기전으로는 caspase-8,3 활성화, Bcl-2 family인 Bid분절, JNK 인산화와 c-Jun 발현이 관여하였다. 결 론 : C-127이 HL-60 세포에서 세포고사를 유도하여 강력한 항암효과를 발현하였고, 그 기전으로 caspase cascade, Bcl-2 family, JNK인산화와 c-Jun활성화가 관여하였다.

Keywords

Acknowledgement

Supported by : Wonkwang University

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