Impair the cellular interferon response or alternatively the effects of TSA go beyond interferon induced antiviral responses. While we cannot distinguish between these possibilities at the present time, the latter explanation seems likely to us since we and others have found using microarray analysis of HDI treated cells, that hundreds of cellular transcripts induced by viral infection are affected by blocking histone deacetylase activity. Using small molecule OV-enhancers is attractive from a clinical standpoint. In principle, this strategy allows for quite significant genetic attenuation of OVs to restrict growth in normal tissues with conditional rescue of the virus replication in SU5416 tumour cells following treatment with an enhancing compound like an HDI or other classes of molecules that can complement viral defects. In this and our previous studies, one of the key features of small molecule complementation of attenuated viruses is that the effect of virus enhancers is restricted to tumour cells with minimal impact on the anti-viral programs of normal tissues. This clearly is the case for TSA in the studies presented here where we demonstrate both in vitro and in animal models that TSA does not enhance virus growth in normal tissues. The reason for this selectivity is unclear at this time however tumour cells are known to have elevated levels of histone deacetylases suggesting that perhaps malignancies have evolved more dependency upon this type of epigenetic modification to control gene expression. Alternatively since tumour cells have often inactivated at least some components of their anti-viral programs, it may be that the addition of HDIs simply “break the camel��s back” in tumour cells but are ineffective in normal tissues that have fully intact multilayered protection systems. Further studies are currently under way to address some of these issues. We GDC-0879 Raf inhibitor conclude that TSA is a potent enhancer of VV in vitro and in vivo. We propose that HDIs such as TSA could be used to enhance the effectiveness of OVs in vivo and that further clinical evaluation of this possibility is warranted. We therefore reasoned that if the AA target was the cytosolic CyP-A, the drug could also act on other members of this protein family. Indeed, such a pleiotropic effect is well-characterized for CsA, as CsA also targets the mitochondria-restricted CyP-D. CyP-D displays an important role in the cell response to a variety of noxious stimuli, as it modulates a channel located in the inner mitochondrial membrane, the permeability transition pore, whose prolonged opening irreversibly commits cells to death. PTP dysregulation is emerging as a common feature in a variety of pathologies endowed with either an excess of cell death, such as neurodegenerative disease or muscular dystrophies, or with an aberrant hyperactivation of survival pathways, as in cancer. CsA inhibits PTP opening through binding to CyP-D. Therefore, it constitutes an interesting molecule for the treatment of degenerative diseases. Nonetheless, due to its immunosuppressant activity, to its side effects and to its inability to pass the blood-brain barrier, CsA analogues with a higher selectivity for CyP-D are under intense scrutiny. Here we demonstrate that, similar to CsA, AA targets CyP-D leading to PTP inhibition and to cell protection from insults that cause pore opening. AA could be exploited as a lead compound for a new class of PTP-inhibiting drugs. The identification of PTP targeting drugs is a highly desirable result, as the PTP is involved in a wide range of diseases. By the use of CsA or of CyP-D knock-out animals it was established that dysregulated.