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: Hossein A Hamed, Adly Yacoub, Margaret A Park, Kellie Archer, Swadesh K Das, Devanand Sarkar, Steven Grant, Paul B Fisher, Paul Dent
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 84 Issue 2 Pg. 171-81 (Aug 2013) ISSN: 1521-0111 [Electronic] United States
• PMID: 23661648 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histone Deacetylase Inhibitors
• Interleukins
• Membrane Proteins
• Reactive Oxygen Species
• interleukin-24
• CERS6 protein, human
• Sphingosine N-Acyltransferase
• Calcium

Topics

• Adenoviridae (metabolism)
• Animals
• Brain Neoplasms (drug therapy, enzymology, metabolism, therapy)
• Calcium (metabolism)
• Cell Line, Tumor
• Cricetinae
• Female
• Genetic Therapy (methods)
• Glioblastoma (drug therapy, metabolism, pathology, therapy)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Interleukins (metabolism)
• Membrane Proteins (metabolism)
• Mice
• Mice, Nude
• Reactive Oxygen Species (metabolism)
• Sphingosine N-Acyltransferase (metabolism)