Synergistic combination of valproic acid and oncolytic parvovirus H‐1 PV as a potential therapy against cervical and pancreatic carcinomas

The rat parvovirus H‐1PV has oncolytic and tumour‐suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co‐treating canc...

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Bibliographic Details
Published in:EMBO molecular medicine 2013-10, Vol.5 (10), p.1537-1555
Main Authors: Li, Junwei, Bonifati, Serena, Hristov, Georgi, Marttila, Tiina, Valmary‐Degano, Séverine, Stanzel, Sven, Schnölzer, Martina, Mougin, Christiane, Aprahamian, Marc, Grekova, Svitlana P., Raykov, Zahari, Rommelaere, Jean, Marchini, Antonio
Format: Article
Language:English
Subjects:
Acetylation
Animal models
Apoptosis
Cancer therapies
Cell cycle
Cervical cancer
Cervical carcinoma
Cervix
Clinical trials
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
Experiments
Gene expression
Histone deacetylase
Infections
Oncolysis
Oxidative stress
Pancreatic cancer
Pancreatic carcinoma
Parvoviruses
Patients
Proteins
Remission
Transcription
Tumor cell lines
Tumors
Valproic acid
Viral infections
Viruses
Xenografts
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Summary:The rat parvovirus H‐1PV has oncolytic and tumour‐suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co‐treating cancer cells with H‐1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H‐1PV/VPA co‐treatment strongly inhibits tumour growth promoting complete tumour remission in all co‐treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1‐mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H‐1PV/VPA co‐treatment against cervical and pancreatic ductal carcinomas.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201302796