TY - JOUR
T1 - Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase
AU - Zigmond, Ehud
AU - Ya'acov, Ami Ben
AU - Lee, Hyunbeom
AU - Lichtenstein, Yoav
AU - Shalev, Zvi
AU - Smith, Yoav
AU - Zolotarov, Lidya
AU - Ziv, Ehud
AU - Kalman, Rony
AU - Le, Hoang V.
AU - Lu, Hejun
AU - Silverman, Richard B.
AU - Ilan, Yaron
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/8/13
Y1 - 2015/8/13
N2 - 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.
AB - 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.
KW - GABA aminotransferase
KW - Hepatocellular carcinoma
KW - alpha fetoprotein
KW - antitumor agent
KW - ornithine aminotransferase
KW - selective inhibitors
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U2 - 10.1021/acsmedchemlett.5b00153
DO - 10.1021/acsmedchemlett.5b00153
M3 - Article
C2 - 26288681
AN - SCOPUS:84938906694
VL - 6
SP - 840
EP - 844
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 8
ER -
