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Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer
Yasuhisa Oida1, Began Gopalan, Ryo Miyahara
1Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Abstract:
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.
Insights
This study shows that combining the melanoma differentiation-associated gene 7 (mda-7) with sulindac enhances antitumor activity against non-small cell lung cancer. The combination therapy increases cancer cell apoptosis and suppresses tumor growth, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Melanoma differentiation-associated gene 7 (mda-7) and sulindac exhibit individual antitumor properties.
- The combined therapeutic effects of mda-7 and sulindac have not been previously investigated.
Purpose of the Study:
- To evaluate the combined antitumor activity of an adenoviral vector expressing mda-7 (Ad-mda7) and sulindac against non-small cell lung cancer (NSCLC).
- To elucidate the underlying mechanisms of enhanced apoptosis and growth suppression in NSCLC cells.
Main Methods:
- In vitro studies using NSCLC cell lines (A549, H1299) and normal lung fibroblasts (CCD-16).
- In vivo studies using human lung tumor xenografts in nude mice.
- Assessment of cell growth, apoptosis, protein expression (MDA-7, RNA-dependent protein kinase, p38MAPK, caspase-9, caspase-3), and protein half-life via pulse-chase experiments.
Main Results:
- Combined Ad-mda7 and sulindac treatment significantly suppressed NSCLC cell growth and induced apoptosis, exceeding the effects of monotherapy.
- The combination therapy demonstrated dose-dependent inhibition of tumor growth with respect to sulindac.
- Sulindac enhanced MDA-7 protein expression by increasing its half-life, leading to upregulated downstream apoptotic effectors.
- No significant growth inhibition was observed in normal lung fibroblasts.
Conclusions:
- Combined Ad-mda7 and sulindac treatment represents a potent strategy for enhancing antitumor activity against NSCLC.
- Increased MDA-7 protein stability is a key mechanism by which sulindac potentiates Ad-mda7-mediated apoptosis.
- This study highlights a novel mechanism involving NSAID-mediated regulation of protein turnover in cancer therapy.
