Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma.

Abstract

Recently, a series of gold(III) meso-tetraarylporphyrins that are stable against demetallation in physiological conditions have been synthesized. In the present study, the antitumor effects of one of these compounds, gold(III) meso-tetraarylporphyrin 1a (gold-1a) was investigated in an orthotopic rat hepatocellular carcinoma (HCC) model as well as using a HCC cell line. The rat HCC model was induced by injection of rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Seven days after tumor cell inoculation, gold-1a was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold-1a administration significantly prolonged the survival of HCC-bearing rats. Importantly, gold-1a induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold-1a treatment neither caused significant drop in body weight of the rats nor affected plasma aspartate aminotransferase level. In the in vitro studies, we observed that gold-1a treatment inhibited the proliferation of McA-RH7777 cells. Gold-1a upregulated genes that increase apoptosis, stabilize p53, decrease proliferation and downregulated genes playing roles in angiogenesis, invasion, and metabolism, as demonstrated by microarray. In particular, the compound upregulated 2 members of the growth arrest and DNA damage (Gadd) inducible gene family, Gadd34 and Gadd153. Suppression of Gadd34 and Gadd153 in McA-RH7777 cells by small hairpin RNA reduced the gold-1a-induced apoptosis and growth inhibition, indicating that gold-1a mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold-1a might be a novel promising chemocytotoxic agent for treating HCC.

• Authors: Ching Tung Lum, Zhen Fan Yang, Hoi Yee Li, Raymond Wai-Yin Sun, Sheung Tat Fan, Ronnie Tung Ping Poon, Marie C M Lin, Chi-Ming Che, Hsiang Fu Kung
• Journal: International journal of cancer (Int J Cancer) Vol. 118 Issue 6 Pg. 1527-38 (Mar 15 2006) ISSN: 0020-7136 [Print] United States
• PMID: 16206274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation
• Cell Cycle Proteins
• Ddit3 protein, rat
• Gold Compounds
• Metalloporphyrins
• gold (III) porphyrin 1a
• Transcription Factor CHOP
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Antigens, Differentiation (genetics, metabolism)
• Apoptosis (drug effects)
• Aspartate Aminotransferases (blood)
• Blotting, Western
• Body Weight (drug effects)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Administration Schedule
• Gene Expression Regulation, Neoplastic (drug effects)
• Gold Compounds (administration & dosage, therapeutic use)
• Injections, Intraperitoneal
• Liver Neoplasms (drug therapy, genetics, pathology)
• Liver Neoplasms, Experimental (drug therapy, genetics, pathology)
• Male
• Metalloporphyrins (administration & dosage, therapeutic use)
• Necrosis (chemically induced)
• Oligonucleotide Array Sequence Analysis
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Time Factors
• Transcription Factor CHOP (genetics, metabolism)