Mcl-1 overexpression in hepatocellular carcinoma: A potential target for antisense therapy

Background/Aims: Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) tissues and its potential role as a molecular drug target for HCC therapy. Methods: HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis. Results: Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect. Conclusions: Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.