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-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.
Lum
Ching Tung
CT
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong, People's Republic of China.
Yang
Zhen Fan
ZF
Li
Hoi Yee
HY
Wai-Yin Sun
Raymond
R
Fan
Sheung Tat
ST
Poon
Ronnie Tung Ping
RT
Lin
Marie C M
MC
Che
Chi-Ming
CM
Kung
Hsiang Fu
HF
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017612:Gold Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000627:therapeutic use*; D009336:Necrosis / Q000139:chemically induced; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; C497251:Ddit3 protein, rat; D017612:Gold Compounds; D008665:Metalloporphyrins; C508665:gold (III) porphyrin 1a; D051742:Transcription Factor CHOP; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase