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

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-tetraaryporphyrin la (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-la was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold-la administration significantly prolonged the survival of HCC-bearing rats. Importantly, gold-la induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold-la 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-la treatment inhibited the proliferation of McA-RH7777 cells. Gold-la 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-la-induced apoptosis and growth inhibition, indicating that gold-la mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold-la might be a novel promising chemocytotoxic agent for treating HCC. (c) 2005 Wiley-Liss. hic.