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Research ArticleArticle

Histone Deacetylase Inhibitors Interact with Melanoma Differentiation Associated-7/Interleukin-24 to Kill Primary Human Glioblastoma Cells

Hossein A. Hamed, Adly Yacoub, Margaret A. Park, Kellie Archer, Swadesh K. Das, Devanand Sarkar, Steven Grant, Paul B. Fisher and Paul Dent
Molecular Pharmacology August 2013, 84 (2) 171-181; DOI: https://doi.org/10.1124/mol.113.086553
Hossein A. Hamed
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Adly Yacoub
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Margaret A. Park
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Kellie Archer
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Swadesh K. Das
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Devanand Sarkar
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Steven Grant
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Paul B. Fisher
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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Paul Dent
Department of Neurosurgery (H.A.H., A.Y., P.D.), Department of Medicine (S.G.), Department of Human and Molecular Genetics (S.K.D., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (M.A.P.), Biostatistics (K.A.), and the VCU Institute of Molecular Medicine (D.S., S.G., P.B.F., P.D.), Virginia Commonwealth University, Richmond, Virginia
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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 Ca2+. Quenching of reactive oxygen species and Ca2+ 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.

Footnotes

    • Received March 27, 2013.
    • Accepted May 9, 2013.
  • This work was supported in part by the Jim Valvano “V” Foundation; the National Institutes of Health National Cancer Institute [Grants P01-CA104177, R01-CA108325, R01-CA63753, R01-CA77141, P01-CA104177, R01-CA097318, and R01-CA134721]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK52825]; and the Department of Defense [Grant DAMD17-03-1-0262].

  • P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research at the VCU Massey Cancer Center. P.D. is The Universal Inc. Chair in Signal Transduction Research.

  • dx.doi.org/10.1124/mol.113.086553.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

MDA-7/IL-24 and GBM

Hossein A. Hamed, Adly Yacoub, Margaret A. Park, Kellie Archer, Swadesh K. Das, Devanand Sarkar, Steven Grant, Paul B. Fisher and Paul Dent
Molecular Pharmacology August 1, 2013, 84 (2) 171-181; DOI: https://doi.org/10.1124/mol.113.086553

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Research ArticleArticle

MDA-7/IL-24 and GBM

Hossein A. Hamed, Adly Yacoub, Margaret A. Park, Kellie Archer, Swadesh K. Das, Devanand Sarkar, Steven Grant, Paul B. Fisher and Paul Dent
Molecular Pharmacology August 1, 2013, 84 (2) 171-181; DOI: https://doi.org/10.1124/mol.113.086553
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