Killing of p53-deficient hepatoma cells by parvovirus H-1 and chemotherapeutics requires promyelocytic leukemia protein

查看全文 作　　者：Maike [1]Sieben;Kerstin [1]Herzer;Maja [1]Zeidler;Vera [1]Heinrichs;Barbara [2]Leuchs;Martin [3]Schuler;Jan J [2]Cornelis;Peter R [1]Galle;Jean [2]Rommelaere;Markus [1]Moehler

机构地区：[1]First Department of Internal Medicine,Johannes Gutenberg University of Mainz;[2]German Cancer Research Center,Infection and Cancer Program,Dept.F010 and Institut National de la Santé et de la Recherche Médicale Unité 701;[3]Department of Medicine (Cancer Research),West German Cancer Center,University Hospital Essen

出　　处：《World Journal of Gastroenterology》索引2008年第14卷第24期,共10页

基　　金：Grants from the German Cancer Aid (Deutsche Krebshilfe) No.10-2183/102322;local university research grants,MAIFOR program,No.9728053 and 9728275 摘　　要：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 cy-totoxicity 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. Further-more,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 morepronounced 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. 关键词：细小病毒细胞凋亡 p53 白血病

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Killing of p53-deficient hepatoma cells by parvovirus H-1 and chemotherapeutics requires promyelocytic leukemia protein

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