We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) in invasive primary human GBM cells. Additionally, a method is described to augment efficacy of adenoviral delivery of mda-7/IL-24 in these cells. HDACIs synergized with MDA-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of ROS and Ca2+. Quenching of ROS and Ca2+ blocked HDACI and MDA-7/IL-24 killing. In vivo MDA-7/IL-24 prolonged survival of animals carrying orthotopic tumors and HDACIs enhanced survival further. A serotype 5/3 adenovirus more effectively delivers mda-7/IL-24 to GBM tumors than a serotype 5 virus. Hence, we constructed a serotype 5/3 adenovirus that conditionally replicates in tumor cells expressing MDA-7/IL-24, in which the adenoviral E1A gene was driven by the cancer-specific promoter progression elevated gene-3 (Ad.5/3-PEG-E1A-mda-7; also called Ad.5/3-CTV). Ad.5/3-CTV increased survival of mice carrying GBM tumors to a significantly greater extent than did a non-replicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrates that HDACIs enhance MDA-7/IL-24 lethality and adenoviral delivery of mda-7/IL-24 combined with tumor specific viral replication is an effective pre-clinical GBM therapeutic.

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