Down-regulation of Mcl-1 with antisense technology alters the effect of various cytotoxic agents used in treatment of squamous cell carcinoma of the head and neck

Abstract

Antisense oligonucleotides have recently been identified as new anticancer agents. Since human head and neck cancer cells highly express the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1), the aim of this study was to explore the efficacy of the Mcl-1 suppression in combination with various cytotoxic agents in the head and neck cancer cell line SCC9. After oligonucleotide transfection and/or treatment with cisplatin, 5-fluorouracil (5-FU), gemcitabine, paclitaxel or cetuximab, proliferation assays were performed to determine cell viability. The expression patterns of Mcl-1, Bax and Bak were assessed by Western blot analysis and the apoptotic cells were determined by immunohistochemistry using the M30 antibody. A combined Mcl-1 antisense oligonucleotide treatment with paclitaxel, cetuximab and gemcitabine led to a significant reduction in the viable cells. However, the combination with cisplatin and 5-FU showed only moderate synergistic cytotoxic effects. According to the cytotoxic data, distinct apoptosis rates were observed after the combined treatment with the different substances. Western blot analysis also showed a significant suppression of the Mcl-1 synthesis. Our data show that the Mcl-1 antisense oligonucleotide in combination with certain cytotoxic agents has the potential to significantly decrease cell viability in vitro.