Therapeutics, Targets, and Chemical Biology A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway Kim Hei-Man Chow 1,2,3 , Raymond Wai-Yin Sun 1 , Janice B.B. Lam 1,2,3 , Carrie Ka-Lei Li 1 , Aimin Xu 2,3 , Dik-Lung Ma 1 , Ruben Abagyan 4 , Yu Wang 1,2 , and Chi-Ming Che 1 Abstract 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 IC 50 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/β-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/β-catenin signaling. Cancer Res; 70(1); 329–37. ©2010 AACR. Introduction Breast cancer represents the most common diagnosed fe- male malignancy and the second leading cause of women death worldwide (1). Chemotherapeutic agents are common- ly used and usually given in the form of combinational che- motherapy (2). However, the effects of these agents are not universal, and a large portion of patients will develop resis- tance. Moreover, side effects including induction of life- threatening toxicity are commonly encountered. Therapeutic values of gold have been recognized thousands of years ago, and its rational use in medicine began in early 1920s (3–7). Because gold(III) is isoelectronic with platinum (II) and tetracoordinate gold(III) complexes are in the same square-planar geometries as cisplatin, the potential antican- cer properties of gold(III) complexes have been investigated for almost three decades (8, 9). A number of gold(III) com- plexes have been reported to exhibit cytotoxicities against a broad spectrum of tumor cells, and their potencies (IC 50 values in low micromolar range) are comparable with that of cisplat- in. In contrast to general expectations, evidence suggest that the gold(III) complexes exert their antiproliferative activities through mechanisms that are substantially different from those of platinum drugs (10). Yet, the molecular mechanisms and targets of gold(III)-based antitumor metallodrugs remain largely uncharacterized. Previously we synthesized a series of gold(III) meso-tetra- arylporphyrin complexes characterized by enhanced stability in aqueous solutions and under physiological conditions (11). Among them, gold-1a [5,10,15,20-tetraphenylporphyrinato gold(III) chloride] showed promising antiproliferative activi- ties against human cancer cells, including those derived from neuroblastoma, colon, nasopharyngeal, and hepatocellular carcinomas (11–15). In the present study, a novel gold(III) porphyrin analogue [5-hydroxyphenyl-10,15,20-triphenylpor- phyrinato gold(III) chloride (gold-2a)] was prepared by mod- ifying one of the peripheral phenyl groups of the gold-1a with a hydroxyl substitution to improve its aqueous solubility (Supplementary Fig. S1). The efficacy of gold-2a in suppres- sing the growth of a panel of human breast cancer cells was evaluated in vitro, and its anticancer activity was investigated in nude mice. Our results suggest that gold-2a is a promising drug lead for anti–breast cancer treatment and that it can selectively inhibit Wnt/β-catenin signaling through modulat- ing histone deacetylase (HDAC) activities. Materials and Methods Preparation of gold(III) porphyrin complex (gold-2a). The synthesis of the gold(III) porphyrin complex (gold-2a) was conducted under a nitrogen atmosphere using the stan- dard Schlenk technique (11). 1 H nuclear magnetic resonance (NMR) spectrum was recorded on a DPX-400 Bruker FT- NMR spectrometer with chemical shift (in ppm) relative to tetramethylsilane. Absorption spectrum was recorded on a Perkin-Elmer Lambda 900 UV-vis spectrophotometer. Mass spectrum (FAB) was recorded on a Finnigan MAT95 mass Cancer Research Authors' Affiliations: 1 Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, Departments of 2 Pharmacology and Pharmacy and 3 Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; and 4 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). K.H-M. Chow and R.W-Y. Sun contributed equally to this work. Corresponding Author: Yu Wang, Department of Pharmacology and Pharmacy, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong. Phone: 852-28192864; Fax: 852-28170859; E-mail: yuwanghk@hku.hk or Chi-Ming Che, Department of Chemistry, the Uni- versity of Hong Kong, Pokfulam Road, Hong Kong. Phone: 852- 28592154; Fax: 852-29155176; E-mail: cmche@hku.hk. doi: 10.1158/0008-5472.CAN-09-3324 ©2010 American Association for Cancer Research. www.aacrjournals.org 329 Downloaded from http://aacrjournals.org/cancerres/article-pdf/70/1/329/2636571/329.pdf by guest on 04 August 2022