title: 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.
authors.affiliation: Department of Radiotherapy and Radiobiology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Skoda
authors.forename: Boban M
authors.initials: BM
authors.lastname: Erovic
authors.forename: Volker
authors.initials: V
authors.lastname: Wachek
authors.forename: Laurenz
authors.initials: L
authors.lastname: Vormittag
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Helga
authors.initials: H
authors.lastname: Martinek
authors.forename: Gregor
authors.initials: G
authors.lastname: Heiduschka
authors.forename: Philipp
authors.initials: P
authors.lastname: Kloimstein
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.forename: Dietmar
authors.initials: D
authors.lastname: Thurnher
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C494772:BAK1 protein, human; C494826:BAX protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; D017239:Paclitaxel; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine