title: Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells.
abstract: In the present study we show that histone deacetylase inhibitors (HDACIs) enhance the anti-tumor effects of melanoma differentiation associated gene-7/interleukin 24 (mda- 7/IL-24) in human renal carcinoma cells. Similar data were obtained in other GU tumor cells. Combination of these two agents resulted in increased autophagy that was dependent on expression of ceramide synthase 6, with HDACIs enhancing MDA-7/IL-24 toxicity by increasing generation of ROS and Ca (2+). Knock down of CD95 protected cells from HDACI and MDA-7/IL-24 lethality. Sorafenib treatment further enhanced (HDACI + MDA-7/IL-24) lethality. Anoikis resistant renal carcinoma cells were more sensitive to MDA-7/IL-24 that correlated with elevated SRC activity and tyrosine phosphorylation of CD95. We employed a recently constructed serotype 5/3 adenovirus, which is more effective than a serotype 5 virus in delivering mda- 7/IL-24 to renal carcinoma cells and which conditionally replicates (CR) in tumor cells expressing MDA-7/IL-24 by virtue of placing the adenoviral E1A gene under the control of the cancer-specific promoter progression elevated gene-3 (Ad.5/3-PEG-E1A-mda-7; CRAd.5/3-mda-7, Ad.5/3-CTV), to define efficacy in renal carcinoma cells. Ad.5/3-CTV decreased the growth of renal carcinoma tumors to a significantly greater extent than did a non-replicative virus Ad.5/3-mda-7. In contralateral uninfected renal carcinoma tumors Ad.5/3-CTV also decreased the growth of tumors to a greater extent than did Ad.5/3-mda-7. In summation, our data demonstrates that HDACIs enhance MDA-7/IL-24-mediated toxicity and tumor specific adenoviral delivery and viral replication of mda-7/IL-24 is an effective pre-clinical renal carcinoma therapeutic.
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Upneet K
authors.initials: UK
authors.lastname: Sokhi
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Park
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Kellie
authors.initials: K
authors.lastname: Archer
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005260:Female; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D000099180:Interleukin-24
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007378:Interleukins; D011994:Recombinant Proteins; D000099180:Interleukin-24
keywords: HDACI; MDA-7/IL-24; ROS; animal study; apoptosis; bystander; caspase; ceramide; cytokine
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