A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

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.

Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

“…The histone acetylation and/or biotinylation at the promoter regions of different genes were analyzed and compared by ChIP-PCR as previously described with modifications (21). In brief, epididymal adipose tissue (100 mg) was minced into small pieces in cold PBS (137 mmol/L NaCl, 4.3 mmol/L Na 2 HPO 4 , 2.7 mmol/L KCl, 1.4 mmol/L KH 2 PO 4 , pH 7.4) with protease inhibitor cocktails.…”

“…Immunoreactive antibody-antigen complexes were visualized with the enhanced chemiluminescence reagents from GE Healthcare (Uppsala, Sweden). For histone modification analysis, histones were extracted from the nuclear fractions of epididymal fat pads following a previously reported procedure (21). In brief, the pellets of nuclei were resuspended overnight in 0.4 mol/L H 2 SO 4 at 4°C.…”

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

“…Since gold(III) ion is isoelectronic with platinum(II) ion and it forms square-planar complexes as in cisplatin, gold(III) compounds are explored for potential anticancer activities. A number of gold(III) complexes with ligands such as bipyridyls, dithiocarbamato, porphyrins, and quinolines, which display in vitro and in vivo potent anticancer activities and reduced systemic toxicity compared with the cisplatin, have been synthesized [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Small peptides such as S-phenylalanine-S-phenylalanine, glycyl-alaline, glycyl-histidine, alanyl-phenylalanine, glycyl-S-serine, glycyl-alanyl-alanine, glycyl-glycyl-histidine, and glycyl-glycyl-methyonyl-glycyl-glycine are another class of ligands of gold(III) ion that have been investigated for development of potential anticancer drugs [18][19][20][21][22][23][24].…”

“…Small peptides such as S-phenylalanine-S-phenylalanine, glycyl-alaline, glycyl-histidine, alanyl-phenylalanine, glycyl-S-serine, glycyl-alanyl-alanine, glycyl-glycyl-histidine, and glycyl-glycyl-methyonyl-glycyl-glycine are another class of ligands of gold(III) ion that have been investigated for development of potential anticancer drugs [18][19][20][21][22][23][24]. Although evidence [10,11,28] suggests that gold-based chemotherapy agents seem to induce antiproliferative activities against tumor cells, the main biological targets and mechanisms responsible for gold-induced cytotoxicity are still largely unknown. However, the interactions between gold-based chemotherapy agents and proteins are believed to be involved in the antitumor activity [10,11,28].…”

“…Although evidence [10,11,28] suggests that gold-based chemotherapy agents seem to induce antiproliferative activities against tumor cells, the main biological targets and mechanisms responsible for gold-induced cytotoxicity are still largely unknown. However, the interactions between gold-based chemotherapy agents and proteins are believed to be involved in the antitumor activity [10,11,28]. Detailed information on the interaction between gold ions and peptides/proteins is needed to shed light on the mechanism of gold compounds' anticancer activity and side effects and facilitate the design of gold-based anticancer agents.…”