Liver Cancer
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Jun 28, 2008; 14(24): 3819-3828
Published online Jun 28, 2008. doi: 10.3748/wjg.14.3819
Killing of p53-deficient hepatoma cells by parvovirus H-1 and chemotherapeutics requires promyelocytic leukemia protein
Maike Sieben, Kerstin Herzer, Maja Zeidler, Vera Heinrichs, Barbara Leuchs, Martin Schuler, Jan J Cornelis, Peter R Galle, Jean Rommelaere, Markus Moehler
Maike Sieben, Kerstin Herzer, Maja Zeidler, Vera Heinrichs, Peter R Galle, Markus Moehler, First Department of Internal Medicine, Johannes Gutenberg University of Mainz, Mainz 55101, Germany
Barbara Leuchs, Jan J Cornelis, Jean Rommelaere, German Cancer Research Center, Infection and Cancer Program, Dept. F010 and Institut National de la Santé et de la Recherche Médicale Unité 701, Heidelberg 69120, Germany
Martin Schuler, Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen 45122, Germany
Author contributions: Sieben M and Herzer K contributed equally to this work; Moehler M corresponds the paper; Sieben M, Herzer K, Zeidler M, Cornelis JJ, Rommelaere J, Moehler M designed research; Herzer K, Zeidler M, Heinrichs V, Leuchs B performed research; Schuler M, Cornelis JJ contributed new reagents/analytic tools; Sieben M, Herzer K, Cornelis JJ, Galle PR, Rommelaere J, Moehler M analyzed data; and Sieben M and Moehler M wrote the paper.
Correspondence to: Markus Moehler, First Department of Internal Medicine of Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, Mainz 55101, Germany.
Telephone: +49-6131-176839
Fax: +49-6131-176621
Received: March 6, 2008
Revised: May 19, 2008
Accepted: May 26, 2008
Published online: June 28, 2008

AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML).

METHODS: The role of p53 and PML in regulating cytotoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Furthermore, H-1 PV infection was combined with cytostatic drug treatment.

RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis, the cytotoxicity of H-1 PV was more pronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses, H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition, H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death.

CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents, and it enhances the apoptotic process which is dependent on functional PML. Thus, H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC, particularly for p53-negative tumors.

Keywords: Autonomous parvovirus, Apoptosis, p53, Promyelocytic leukemia protein, Human hepatocellular carcinoma, Hepatocytes