title: Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells.
abstract: Gastric cancer is the second most common cause of death from cancer worldwide and resistant to various chemotherapeutic regimens. In gastric cancer, the anti-apoptotic Mcl-1 protein is expressed in up to 75% of all cases and associated with poor prognosis. The biological relevance of Mcl-1 expression in gastric cancer is unclear. Thus, we investigated the functional significance and potential role of Mcl-1 as a molecular target in gastric cancer by using an antisense strategy. Gastric cancer cell lines (NCI-N87, MKN-28, MKN-45) were treated with Mcl-1 antisense oligonucleotides. Protein expression, cell growth and apoptosis were assessed for single-agent Mcl-1 AS oligonucleotide treatment and for combinations with docetaxel or cisplatin. Treatment by Mcl-1 AS oligonucleotides resulted in approximately 50% reduction in Mcl-1 protein levels in all gastric cancer cell lines examined. Surprisingly, dose-dependent Mcl-1 downregulation produced a significant increase in apoptosis and up to 60% decrease in cell growth. Moreover, combination of Mcl-1 AS oligonucleotide with docetaxel or cisplatin displayed synergistic anti-tumor activity. In conclusion, the impressive single-agent anti-tumor activity and the synergistic effect of Mcl-1 AS oligonucleotides in combination with chemotherapy might qualify Mcl-1 as a promising molecular target for AS oligonucleotide based treatment strategies for gastric cancer in the future.
authors.affiliation: Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Medical University Vienna, Vienna, Austria. volker.wacheck@meduniwien.ac.at
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.forename: Daniel
authors.initials: D
authors.lastname: Cejka
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.forename: Doris
authors.initials: D
authors.lastname: Losert
authors.forename: Sabine
authors.initials: S
authors.lastname: Strommer
authors.forename: Richard
authors.initials: R
authors.lastname: Crevenna
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D013274:Stomach Neoplasms / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin