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 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(4)Phen)OH(2)](ClO(4))(2), and Ru(bpy)(2)Cl(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.
Wang
Yun-Hsin
YH
Graduate Institute of Life Sciences, Tamkang University, No. 151 Ying-chuan Road, Tamsui 251, Taipei County, Taiwan.
Cheng
Chien-Chung
CC
Lee
Wen-Jie
WJ
Chiou
Min-Lun
ML
Pai
Chiung-Wen
CW
Wen
Chi-Chung
CC
Chen
Wei-Li
WL
Chen
Yau-Hung
YH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008856:Microscopy, Fluorescence; D008857:Microscopy, Interference; D016328:NF-kappa B / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010641:Phenotype; D012428:Ruthenium / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish
D000970:Antineoplastic Agents; D016328:NF-kappa B; D009942:Organometallic Compounds; D016159:Tumor Suppressor Protein p53; D012428:Ruthenium; D002945:Cisplatin