1. Synergistic combination of valproic acid and oncolytic parvovirus H‐1PV as a potential therapy against cervical and pancreatic carcinomas
H‐1PV and VPA synergize against cancer: a tentative model Multiple mechanisms of action are thought to play a role in the enhanced anticancer effect observed by combining H‐1PV with VPA. On the one hand, VPA and H‐1PV (through NS1) induce accumulation of intracellular reactive oxygen species (ROS). This oxidative stress overwhelms antioxidant mechanisms leading to increased DNA damage, apoptosis and cell lysis. On the other hand, VPA treatment is associated with hyper‐acetylation of the viral NS1 protein which is converted in a more active peptide. Acetylated NS1 binds more efficiently to viral DNA, leading to increased viral DNA replication and viral gene transcription. This ultimately results in enhanced viral multiplication in permissive cancer cells. Viral progeny particles infect neighbouring cancer cells and participate in the complete tumour remission observed in animal models. An additional component not documented by the present study, may involve the VPA‐mediated modulation of cellular defence mechanisms (not shown in scheme). Abbr. NS1: parvovirus nonstructural NS1 protein; PV‐ds DNA: H‐1PV double stranded DNA replicative form; P4: H‐1PV early promoter; P38: H‐1PV late promoter; NS: transcription unit encoding the nonstructural NS proteins; VP: transcription unit encoding the VP capsid proteins; VPA: valproic acid.
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EMBO Mol Med, Volume: 5, Issue: 10, Pages: , First published: 17 September 2013, DOI: ( /emmm )