A gold(III) porphyrin complex with antitumor properties targets the Wnt/beta-catenin pathway.
Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/beta-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/beta-catenin signaling.
Chow
Kim Hei-Man
KH
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam, Hong Kong, China.
Sun
Raymond Wai-Yin
RW
Lam
Janice B B
JB
Li
Carrie Ka-Lei
CK
Xu
Aimin
A
Ma
Dik-Lung
DL
Abagyan
Ruben
R
Wang
Yu
Y
Che
Chi-Ming
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D017612:Gold Compounds / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D013058:Mass Spectrometry; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects
D000970:Antineoplastic Agents; D017612:Gold Compounds; D056572:Histone Deacetylase Inhibitors; D008665:Metalloporphyrins; D051153:Wnt Proteins; D051176:beta Catenin