Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase.
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.
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Ehud
E
Zigmond
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Ami
A
Ben Ya'acov
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
Hyunbeom
H
Lee
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Yoav
Y
Lichtenstein
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Zvi
Z
Shalev
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Yoav
Y
Smith
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Lidya
L
Zolotarov
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Ehud
E
Ziv
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Rony
R
Kalman
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
Hoang V
HV
Le
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
Hejun
H
Lu
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
Richard B
RB
Silverman
Liver Unit, Genomic Data Analysis Unit, and Diabetes Unit, Faculty of Medicine, Hebrew University-Hadassah Medical Center , Jerusalem 91120, Israel.
Yaron
Y
Ilan
GABA aminotransferase; Hepatocellular carcinoma; alpha fetoprotein; antitumor agent; ornithine aminotransferase; selective inhibitors