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

Abstract

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.

Standardized large-scale H-1PV production process with efficient quality and quantity monitoring

“…This trial is expected to be followed by further clinical studies aiming to assess efficacy and to extend the approach to other cancers such as pancreatic carcinoma or neuroblastoma (Lacroix et al, 2010;Li et al, 2013). These developments rely on the availability of robust procedures for protoparvovirus production and characterization.…”

“…Current research in our lab aims at developing a portfolio of modified oncolytic protoparvoviruses, vector derivatives, and protoparvovirus combination treatments with enhanced anticancer action (Li et al, 2013;Weiss et al, 2012). These developments should yield proofs of concept to be put to the clinical test.…”

“…The virus thus has oncolytic and oncosuppressive properties that have been demonstrated in various cell cultures and animal models (Nuesch et al, 2012;Rommelaere et al, 2010). In xenograft models, H-1PV has been shown to suppress a number of human tumors, including cervical tumors (Faisst et al, 1998;Li et al, 2013), pancreatic tumors (Angelova et al, 2009b;Grekova et al, 2011), mammary carcinomas (Dupressoir et al, 1989), gliomas Kiprianova et al, 2011), and lymphomas (Angelova et al, 2009a). On the basis of these preclinical proofs of concept, a first clinical trial (phase I/IIa) of H-1PV ParvOryx01 (clinical trial identifier NCT01301430) was launched in 2011 in patients with recurrent glioblastoma multiforme (Geletneky et al, 2012),…”

Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

“…However, the HDAC inhibitory mechanism of VPA is relatively well known. [8][9][10] HDAC is reported to be aberrantly expressed in diverse cancers. HDAC inhibition can increase the expression of several genes by accelerating their transcription, which can enhance the innate immune system and lead to suppression of tumor growth.…”

“…However, a synergistic effect of VPA with other agents has been reported in some promising results. [8][9][10] VPA upregulates MIC-A and MIC-B, 11 and this upregulation on the tumor surface enhances CIK cells effects. Moreover, VPA has been safely used as an antiepileptic drug for decades, it is relatively inexpensive, and its adverse effects have been regarded as tolerable.…”