Hepatocellular carcinoma is the second leading cause of
cancer death worldwide.
DNA microarray analysis identified the
ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in
hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by
gabaculine (1), a neurotoxic
natural product, which suppressed in vitro proliferation of two HCC cell lines.
Alpha-fetoprotein (AFP) secretion, a
biomarker for HCC, was suppressed by
gabaculine in both cell lines, but not significantly. Because of the active site similarity between
GABA aminotransferase (
GABA-AT) and OAT, a library of 24
GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic
acid (2) was found to be an inactivator of OAT that only weakly inhibits
GABA-AT,
l-aspartate aminotransferase, and
l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and
tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.