Melanoma differentiation-associated 7 (interleukin 24) inhibits growth and enhances radiosensitivity of glioma cells in vitro and in vivo.

Abstract

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: Adly Yacoub, Clint Mitchell, Andrea Lister, Irina V Lebedeva, Devanand Sarkar, Zao-Zhong Su, Carter Sigmon, Robert McKinstry, Viswanathan Ramakrishnan, Liang Qiao, William C Broaddus, Rahul V Gopalkrishnan, Steven Grant, Paul B Fisher, Paul Dent
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 9 Pg. 3272-81 (Aug 15 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12960112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BAX protein, human
• BCL2L1 protein, human
• Bax protein, rat
• Bcl2l1 protein, rat
• Interleukins
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Radiation-Sensitizing Agents
• Tetrazolium Salts
• Thiazoles
• bcl-2-Associated X Protein
• bcl-X Protein
• interleukin-24
• Glutathione Transferase
• thiazolyl blue
• Acetylcysteine

Topics

• Acetylcysteine (metabolism)
• Adenoviridae (genetics)
• Animals
• Astrocytes (drug effects, radiation effects)
• Blotting, Western
• Brain Neoplasms (metabolism, radiotherapy, therapy)
• Cell Division (drug effects, radiation effects)
• Cell Line
• Cell Line, Tumor
• Cell Survival
• Cells, Cultured
• DNA Fragmentation
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Down-Regulation
• Gene Transfer Techniques
• Genes, Tumor Suppressor
• Glioblastoma (metabolism, radiotherapy, therapy)
• Glioma (drug therapy, metabolism, radiotherapy)
• Glutathione Transferase (metabolism)
• Humans
• Interleukins (genetics, metabolism)
• Necrosis
• Proto-Oncogene Proteins (biosynthesis)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Radiation-Sensitizing Agents (therapeutic use)
• Rats
• Rats, Inbred F344
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• bcl-2-Associated X Protein
• bcl-X Protein