Sulindac enhances adenoviral vector expressing mda-7/IL-24–mediated apoptosis in human lung cancer

Several studies have shown antitumor activities of the melanoma differentiation–associated gene 7 ( mda-7 ) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previous...

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Published in:Molecular cancer therapeutics 2005-02, Vol.4 (2), p.291-304
Main Authors: Oida, Yasuhisa, Gopalan, Began, Miyahara, Ryo, Inoue, Satoshi, Branch, Cynthia D, Mhashilkar, Abner M, Lin, E, Bekele, B Nebiyou, Roth, Jack A, Chada, Sunil, Ramesh, Rajagopal
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Cell Cycle - drug effects
Cell Line, Tumor
Gene Therapy
Genes, Tumor Suppressor
Genetic Vectors - genetics
Humans
IL-24
Interleukins - genetics
Interleukins - metabolism
Lung cancer
Lung Neoplasms - metabolism
MDA-7
Mice
Mice, Nude
NSAID
Proteasome Endopeptidase Complex - drug effects
Signal Transduction - genetics
Sulindac
Sulindac - pharmacology
Transduction, Genetic
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Summary:Several studies have shown antitumor activities of the melanoma differentiation–associated gene 7 ( mda-7 ) and the nonsteroidal anti-inflammatory drug sulindac when used as a monotherapies against a wide variety of human cancers. However, the combined effects of mda-7 and sulindac have not previously been tested. Therefore, we tested the antitumor activity of an adenoviral vector expressing mda-7 (Ad-mda7) in combination with sulindac against non–small cell lung cancer cells in vitro and in vivo . When treated with Ad-mda7 in combination with sulindac, human lung cancer cells (A549 and H1299) underwent growth suppression resulting in apoptosis. The growth inhibition induced by Ad-mda7 in combination with sulindac was significantly greater than that observed with Ad-mda7 or sulindac alone. Furthermore, the degree of growth inhibition induced using this combination was dose-dependent for sulindac. Treatment with Ad-mda7 in combination with sulindac had no growth inhibitory effects on human normal lung (CCD-16) fibroblasts. We then investigated the mechanism by which sulindac enhances Ad-mda7-mediated apoptosis. Sulindac increased expression of ectopic MDA-7 protein in tumor cells, thereby increasing the expression of downstream effectors RNA-dependent protein kinase, p38MAPK, caspase-9, and caspase-3 and enhancing apoptosis of non–small cell lung cancer cells. Pulse-chase experiments showed that the increased expression of MDA-7 protein in sulindac-treated cells was due to increased half-life of the MDA-7 protein. Finally, treatment of human lung tumor xenografts in nude mice with Ad-mda7 plus sulindac significantly suppressed growth ( P = 0.001) compared with Ad-mda7 or sulindac alone. Our results show for the first time that combined treatment with Ad-mda7 plus sulindac enhances growth inhibition and apoptosis of human lung cancer cells. The increased antitumor activity observed with the combination treatment is a result of increased half-life of MDA-7 protein. Regulation of protein turnover is a heretofore-unrecognized mechanism of this nonsteroidal anti-inflammatory drug.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.291.4.2