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.
MeSH terms
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal, Humanized
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects*
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Apoptosis / physiology
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Blotting, Western
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Cetuximab
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Cisplatin / administration & dosage
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Combined Modality Therapy
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Deoxycytidine / administration & dosage
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Deoxycytidine / analogs & derivatives
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Down-Regulation
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Fluorouracil / administration & dosage
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Gemcitabine
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / metabolism
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Humans
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Immunoenzyme Techniques
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Myeloid Cell Leukemia Sequence 1 Protein
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Oligonucleotides, Antisense / pharmacology
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Paclitaxel / administration & dosage
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Tumor Cells, Cultured
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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BAK1 protein, human
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BAX protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins c-bcl-2
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Deoxycytidine
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Paclitaxel
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Cetuximab
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Cisplatin
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Fluorouracil
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Gemcitabine