Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase

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• 作者：Ehud Zigmond ; Ami Ben Ya鈥檃cov ; Hyunbeom Lee ; Yoav Lichtenstein ; Zvi Shalev ; Yoav Smith ; Lidya Zolotarov ; Ehud Ziv ; Rony Kalman ; Hoang V. Le ; Hejun Lu ; Richard B. Silverman ; Yaron Ilan
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：840-844
• 全文大小：287K
• ISSN：1948-5875

文摘

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.