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KMID : 1130320090520060696
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Korean Journal of Pediatrics
2009 Volume.52 No. 6 p.696 ~ p.700
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Anti-tumor effect of new compound, 127, through the induction of apoptosis
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Baik Ki-Hwan
Yu Seung-Taek
Kim Jong-Duk
Yoon Young-Wook
Choi Du-Young
Han A-Lum
Shin Sae-Ron
Jin Chun-Mae
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Abstract
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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.
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KEYWORD
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Compound-127, Endoperoxide ring, Artemisinin, Leukemia apoptosis
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