Study of the Acquisition of Sensitivity to Paclitaxel Plus Cetuximab by the Addition of Low-dose Proteasome Inhibitor.

Abstract

Although paclitaxel plus cetuximab for recurrent/metastatic oral squamous cell carcinoma (OSCC) has a relatively high success rate, many cases are refractory. We investigated the change in nuclear factor-kappa B (NF-B) expression after this combination therapy using microcollagen 3D cell culture. We also investigated changes in antitumor efficacy using low doses of paclitaxel-cetuximab combined with the proteasome inhibitor bortezomib on a cell line with low sensitivity to paclitaxel plus cetuximab. Eight human OSCC cell lines were cultured in 3D and exposed to paclitaxel-cetuximab. real-time polymerase chain reaction was used to evaluate NF-B mRNA expression in OSCC cell lines in vivo and in vitro after exposure to anticancer agents. Activity at the protein level was confirmed using western blotting. Bortezomib (0.002-0.4 μg/ml) was added to paclitaxel-cetuximab and its effects assessed in OSCC cell lines with low paclitaxel-cetuximab sensitivity. mRNA and protein expression of NF-B was significantly reduced after treatment with paclitaxel-cetuximab in cell lines sensitive to this combination. In contrast, both mRNA and protein expression significantly increased in the cell lines with low sensitivity to paclitaxel plus cetuximab. The addition of low concentrations of bortezomib to cell lines with low sensitivity to paclitaxel-cetuximab was found to enhance antitumor efficacy. Increased NF-B expression strongly contributes to resistance to paclitaxel-cetuximab, suggesting that the administration of small doses of bortezomib, which inhibits NF-B, combined with paclitaxel-cetuximab may enhance antitumor efficacy against cancer cells with low sensitivity to the combination therapy.