PURPOSE: Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. EXPERIMENTAL DESIGN: Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines. RESULTS: Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-(XL) and enhanced expression of BAX. Overexpression of Bcl-(XL) protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7. CONCLUSIONS: These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.
PURPOSE: Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. EXPERIMENTAL DESIGN:Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines. RESULTS: Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-(XL) and enhanced expression of BAX. Overexpression of Bcl-(XL) protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7. CONCLUSIONS: These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.
Authors: Luni Emdad; Devanand Sarkar; Irina V Lebedeva; Zao-Zhong Su; Pankaj Gupta; Parameshwar J Mahasreshti; Paul Dent; David T Curiel; Paul B Fisher Journal: J Cell Physiol Date: 2006-08 Impact factor: 6.384
Authors: Paul Dent; Adly Yacoub; Hossein A Hamed; Margaret A Park; Rupesh Dash; Sujit K Bhutia; Devanand Sarkar; Xiang-Yang Wang; Pankaj Gupta; Luni Emdad; Irina V Lebedeva; Moira Sauane; Zhao-zhong Su; Mohamed Rahmani; William C Broaddus; Harold F Young; Maciej S Lesniak; Steven Grant; David T Curiel; Paul B Fisher Journal: Pharmacol Ther Date: 2010-08-21 Impact factor: 12.310
Authors: Paul Dent; Adly Yacoub; Hossein A Hamed; Margaret A Park; Rupesh Dash; Sujit K Bhutia; Devanand Sarkar; Pankaj Gupta; Luni Emdad; Irina V Lebedeva; Moira Sauane; Zhao-Zhong Su; Mohamed Rahmani; William C Broaddus; Harold F Young; Maciej Lesniak; Steven Grant; David T Curiel; Paul B Fisher Journal: Anticancer Drugs Date: 2010-09 Impact factor: 2.248
Authors: Maria G Castro; Marianela Candolfi; Thomas J Wilson; Alexandra Calinescu; Christopher Paran; Neha Kamran; Carl Koschmann; Mariela A Moreno-Ayala; Hikmat Assi; Pedro R Lowenstein Journal: Expert Opin Biol Ther Date: 2014-04-29 Impact factor: 4.388
Authors: Adly Yacoub; Margaret A Park; Pankaj Gupta; Mohammed Rahmani; Guo Zhang; Hossein Hamed; David Hanna; Devanand Sarkar; Irina V Lebedeva; Luni Emdad; Moira Sauane; Nicollaq Vozhilla; Sarah Spiegel; Costas Koumenis; Martin Graf; David T Curiel; Steven Grant; Paul B Fisher; Paul Dent Journal: Mol Cancer Ther Date: 2008-02 Impact factor: 6.261
Authors: Margaret A Park; Adly Yacoub; Devanand Sarkar; Luni Emdad; Mohammed Rahmani; Sarah Spiegel; Costas Koumenis; Martin Graf; David T Curiel; Steven Grant; Paul B Fisher; Paul Dent Journal: Autophagy Date: 2008-02-13 Impact factor: 16.016