Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase

Ehud Zigmond, Ami Ben Ya'acov, Hyunbeom Lee, Yoav Lichtenstein, Zvi Shalev, Yoav Smith, Lidya Zolotarov, Ehud Ziv, Rony Kalman, Hoang V. Le, Hejun Lu, Richard B. Silverman*, Yaron Ilan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)840-844
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number8
DOIs
StatePublished - Aug 13 2015

Keywords

  • GABA aminotransferase
  • Hepatocellular carcinoma
  • alpha fetoprotein
  • antitumor agent
  • ornithine aminotransferase
  • selective inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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