A novel phenotype-based approach for systematically screening antiproliferation metallodrugs.

Abstract

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.

• Authors: Yun-Hsin Wang, Chien-Chung Cheng, Wen-Jie Lee, Min-Lun Chiou, Chiung-Wen Pai, Chi-Chung Wen, Wei-Li Chen, Yau-Hung Chen
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 182 Issue 1 Pg. 84-91 (Nov 10 2009) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 19682442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Organometallic Compounds
• Tumor Suppressor Protein p53
• Ruthenium
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Screening Assays, Antitumor (methods)
• Embryo, Nonmammalian (drug effects)
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Microscopy, Fluorescence
• Microscopy, Interference
• NF-kappa B (metabolism)
• Organometallic Compounds (pharmacology)
• Phenotype
• Ruthenium (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Zebrafish