Sulindac Induces Apoptosis and Inhibits Tumor Growth In Vivo in Head and Neck Squamous Cell Carcinoma

Abstract

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.

In Vivo Antineoplastic Effects of the NSAID Sulindac in an Oral Carcinogenesis Model

“…These propapoptotic effects have been shown to be mediated through downregulation of survivin activity (25,26). In accordance with these findings, our current results also indicate that sulindac decreases survivin expression in vivo, in all stages of carcinogenesis in the HOCM.…”

“…Taken together, the results of this study in the face of the available literature (25,26) may support the ability of sulindac to downregulate cell proliferation and survivin expression in the HOCM, which may provide a molecular explanation for its potent antineoplastic properties in the HOCM.…”

“…Furthermore, it may be proved helpful as an adjuvant chemotherapeutic factor in patients with oral SCC. We consider that the results of this study taken together with the results of the aforementioned in vitro (21,25,26) and in vivo (26,36) studies pave the way for clinical trials.…”

“…An in vivo study in athymic nude mice that developed tumors after subcutaneous injection of HEP-2 cells showed significant regression of HEP-2 xenograft growth in sulindac-treated mice and downregulation of survivin protein levels in sulindac-treated tumors versus untreated control mice (26).…”

“…Furthermore, it has been shown that cell growth inhibition of apoptosis and survivin downmodulation is a specific effect of sulindac that is not shared by other COX inhibitors and that survivin is a downstream target and effector of oncogenic Stat3 signaling in oral SSC, which is targeted by sulindac in a COX-2-independent manner (25). An in vivo study in athymic nude mice that developed tumors after subcutaneous injection of HEP-2 SCC cells showed significant regression of HEP-2 xenograft growth and downregulation of survivin protein levels in sulindac-treated mice versus untreated control mice (26).…”