Genome-wide study of the anti-tumor effect of gold-1a, a novel chemo-cytotoxic agent for hepatocellular carcinoma (HCC)

Abstract

Hepatocellular Carcinoma (HCC) is often diagnosed at an advancedstage that it is no longer surgically resectable. Therefore, novel andeffective chemotherapy agents are urgently needed. We have recentlyshown that gold (III) meso-tetraarylporphyrin 1a (gold-1a) is a poten-tially promising chemotherapeutic drug to treat HCC (Lum et al., IntJ Cancer, in press). Here, we investigate the molecular mechanism ofthe anti-tumor effect of gold-1a by genome-wide cDNA microarrayand bioinformatic approaches. In rat hepatoma McA-RH7777 cells,Gold-1a treatment induced apoptosis through the expressions ofCaspase 3, 6, and 12. It up-regulated pathways in G1 phase cell cyclecontrol through Myc and SMAD 4,7 signaling, and promote DNArepair through Gadd34 and Gadd153 (members of the growth arrestand DNA-damage-inducible family). Furthermore, Gold-1a sup-pressed the expression of an angiogenesis gene Serpine1 and inhib-ited microvessel endothelial cell proliferation and microvessel tubeformation. Consistent with results from the genome wide in vitrostudies, we showed that Gold-1a treatment not only enhanced tumorapoptosis and necrosis, but also reduced microvessel density in tumortissues in an in vivo study in a rat orthotopic HCC model. Based onthe expression data and the known protein-protein interaction, weelucidated the global signal transduction pathways that lead to thepotent anti-tumor effect of Gold-1a.