Published online Jun 28, 2008. doi: 10.3748/wjg.14.3819
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.