title: Histone deacetylase inhibitors interact with melanoma differentiation associated-7/interleukin-24 to kill primary human glioblastoma cells.
abstract: 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 glioblastoma multiforme (GBM) cells. Additionally, a method is described to augment the efficacy of adenoviral delivery of mda-7/IL-24 in these cells. HDACIs synergized with melanoma differentiation-associated (MDA)-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on the expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of reactive oxygen species and Ca(2+). Quenching of reactive oxygen species and Ca(2+) blocked HDACI and MDA-7/IL-24 killing. In vivo MDA-7/IL-24 prolonged the 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 early region 1A (E1A) gene was driven by the cancer-specific promoter progression elevated gene-3 [Ad.5/3 (INGN 241)-PEG-E1A-mda-7; also called Ad.5/3-CTV (cancer terminator virus)]. Ad.5/3-CTV increased the survival of mice carrying GBM tumors to a significantly greater extent than did a nonreplicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrate 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 preclinical GBM therapeutic.
authors: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
authors: Hossein A
authors: HA
authors: Hamed
authors: Adly
authors: A
authors: Yacoub
authors: Margaret A
authors: MA
authors: Park
authors: Kellie
authors: K
authors: Archer
authors: Swadesh K
authors: SK
authors: Das
authors: Devanand
authors: D
authors: Sarkar
authors: Steven
authors: S
authors: Grant
authors: Paul B
authors: PB
authors: Fisher
authors: Paul
authors: P
authors: Dent
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D002118:Calcium; D056572:Histone Deacetylase Inhibitors; D007378:Interleukins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D051049:Sphingosine N-Acyltransferase; D000099180:Interleukin-24; C506123:CERS6 protein, human
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