A novel phenotype-based approach for systematically screening antiproliferation metallodrugs

Ruthenium (Ru) derivatives have less toxicity and higher water-solubility than cisplatin, giving them great potential as antitumor metallodrugs. In this study, zebrafish were employed as a whole-organism model to screen new Ru compounds for anti-cell proliferation activity. After soaking fish embryo...

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Veröffentlicht in:Chemico-biological interactions 2009-11, Vol.182 (1), p.84-91
Hauptverfasser: Wang, Yun-Hsin, Cheng, Chien-Chung, Lee, Wen-Jie, Chiou, Min-Lun, Pai, Chiung-Wen, Wen, Chi-Chung, Chen, Wei-Li, Chen, Yau-Hung
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Sprache:eng
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Zusammenfassung:Ruthenium (Ru) derivatives have less toxicity and higher water-solubility than cisplatin, giving them great potential as antitumor metallodrugs. In this study, zebrafish were employed as a whole-organism model to screen new Ru compounds for anti-cell proliferation activity. After soaking fish embryos in cisplatin and five Ru derivatives, [Ru(terpy)(bpy)Cl]Cl, [Ru(terpy)(dppz)OH 2](ClO 4) 2, [Ru(terpy)(tMen)OH 2](ClO 4) 2, [Ru(terpy)(Me 4Phen)OH 2](ClO 4) 2, and Ru(bpy) 2Cl 2, only cisplatin and [Ru(terpy)(bpy)Cl]Cl-treated embryos displayed obvious phenotypic effects, such as fin-reduction. After further modification of [Ru(terpy)(bpy)Cl]Cl's main structure and the synthesis of two structurally related compounds, [Ru(terpy)(dcbpyH 2)Cl]Cl and [Ru(terpy)(dmbpy)Cl]Cl, only [Ru(terpy)(dmbpy)Cl]Cl exhibited fin-reduction phenotypes. TUNEL assays combined with immunostaining techniques revealed that treatment with cisplatin, [Ru(terpy)(bpy)Cl]Cl, and [Ru(terpy)(dmbpy)Cl]Cl led proliferating fin mesenchymal cells to undergo apoptosis and consequently caused fin-reduction phenotypes. Furthermore, [Ru(terpy)(bpy)Cl]Cl was able to activate the P53-dependent and independent pathways, and induced human hepatoma cells to undergo apoptosis. In summary, it was concluded that the zebrafish model was effective for the screening of phenotype-based antiproliferation metallodrugs.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2009.08.005