Sulindac induces apoptosis and inhibits tumor growth in vivo in head and neck squamous cell carcinoma.
Sulindac has antineoplastic effects on various cancer cell lines; consequently, we assessed sulindac's effects on laryngeal squamous cell carcinoma (SCC) cells in vitro and in vivo. In vitro, SCC (HEP-2) cells treated with various cyclooxygenase inhibitors or transfected with constitutively active signal transducer and activator of transcription 3 (Stat3) or survivin vectors were analyzed using Western blot analysis, annexin V assay, and cell proliferation assay. In parallel, nude mice injected subcutaneously with HEP-2 cells were either treated intraperitoneally with sulindac or left untreated, and analyzed for tumor weight, survivin expression, and tyrosine-phosphorylated Stat3 expression. In vitro studies confirmed the selective antiproliferative and proapoptotic effects of sulindac, which also downregulated Stat3 and survivin protein expression. Stat3 or survivin forced expression partially rescued the antiproliferative effects of sulindac. In vivo studies showed significant repression of HEP-2 xenograft growth in sulindactreated mice versus controls, with near-complete resolution at 10 days. Additionally, tumor specimens treated with sulindac showed downregulation of phosphorylated tyrosine-705 Stat3 and survivin expression. Taken together, our data suggest, for the first time, a specific inhibitory effect of sulindac on tumor growth and survivin expression in laryngeal cancer, both in vitro and in vivo, in a Stat3-dependent manner, suggesting a novel therapeutic approach to head and neck cancer.
Scheper
Mark A
MA
Department of Diagnostic Sciences and Pathology, University of Maryland, Baltimore, MD 21201, USA. mscheper@umaryland.edu
Nikitakis
Nikolaos G
NG
Chaisuparat
Risa
R
Montaner
Silvia
S
Sauk
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D013467:Sulindac / Q000494:pharmacology / Q000627:therapeutic use*; D000077022:Survivin; D014183:Transplantation, Heterologous
C107489:BIRC5 protein, human; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D013467:Sulindac