The effect of indomethacin on paclitaxel sensitivity and apoptosis in oral squamous carcinoma cells: the role of nuclear factor-kappaB inhibition.

摘要

OBJECTIVE: To investigate new strategies to intensify chemosensitivity in head and neck squamous cell carcinoma. DESIGN: Oral squamous carcinoma cells were examined for nuclear factor-kappaB (NF-kappaB) activation and binding activity by paclitaxel, an agent currently used in head and neck cancer chemotherapy. Electromobility shift assays were used to assess the effect of indomethacin on NF-kappaB binding activity. Cell proliferation assays were used to study cell sensitivity to paclitaxel. To examine whether cytotoxicity could be increased by specifically inhibiting NF-kappaB, a dominant negative cell line, inhibitor kappa B-alpha (IkappaBalpha), was stably expressed in CA-9-22 cells. RESULTS: Paclitaxel possessed the capacity to functionally activate NF-kappaB, as demonstrated by luciferase reporter gene assays and electromobility shift assay. Indomethacin was able to inhibit paclitaxel-mediated NF-kappaB activation and promote apoptosis of paclitaxel-treated cells at 24 hours. Indomethacin augmented the paclitaxel cell-killing effect. The dominant negative IkappaBalpha cell line exhibited increased chemosensitization to paclitaxel by 2- to 10-fold. CONCLUSIONS: Paclitaxel has the capacity to activate NF-kappaB in oral squamous carcinoma cells. Indomethacin can reverse this activation to decrease cell proliferation and increase apoptosis. Treatment strategies that combine paclitaxel with indomethacin may have therapeutic benefits attributable to paclitaxel chemosensitization through NF-kappaB inhibition.