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 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.
Oida
Yasuhisa
Y
Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Gopalan
Began
B
Miyahara
Ryo
R
Inoue
Satoshi
S
Branch
Cynthia D
CD
Mhashilkar
Abner M
AM
Lin
E
E
Bekele
B Nebiyou
BN
Roth
Jack A
JA
Chada
Sunil
S
Ramesh
Rajagopal
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics; D013467:Sulindac / Q000494:pharmacology*; D014161:Transduction, Genetic; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D007378:Interleukins; D046988:Proteasome Endopeptidase Complex; D013467:Sulindac; D000099180:Interleukin-24