This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Oida, Y. Articles by Ramesh, R. Search for Related Content PubMed PubMed Citation Articles by Oida, Y. Articles by Ramesh, R.

Departments of ¹ Thoracic and Cardiovascular Surgery, ² Biostatistics, and ³ Experimental Therapeutics, University of Texas M. D. Anderson Cancer, Center; and ⁴ Introgen Therapeutics, Inc., Houston, Texas

Requests for reprints: Rajagopal Ramesh, Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-9144; Fax: 713-794-4901. E-mail: rramesh{at}mdanderson.org

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.

Key Words: MDA-7 • IL-24 • Sulindac • NSAID • Lung cancer • Apoptosis • Gene Therapy

Grant support: NIH/National Cancer Institute grants RO1-CA102716 and PO1 CA06294 (R. Ramesh), and CA89778, CA88421, CA097598 (S. Chada); Cancer Center support grant CA16672; Texas Higher Education Coordinating Board ATP/ARP grant 003657-0078-2001; institutional research grant from University of Texas M.D. Anderson Cancer Center; and sponsored research agreement with Introgen Therapeutics, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ B. Gopalan, S. Sharma, A. Litrak, S. Chada, and R. Ramesh, unpublished data.

⁶ Unpublished data.

Received 10/26/04; revised 12/ 1/04; accepted 12/30/04.