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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Rausch, V; Liu, L; Kallifatidis, G; Baumann, B; Mattern, J; Gladkich, J; Wirth, T; Schemmer, P; Büchler, MW; Zöller, M; Salnikov, AV; Herr, I.
Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics.
Cancer Res. 2010; 70(12):5004-5013 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Schemmer Peter
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Abstract:
Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappaB associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappaB activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappaB binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO.
Find related publications in this database (using NLM MeSH Indexing)
Aldehyde Dehydrogenase - metabolism
Animals -
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Apoptosis - drug effects
Benzenesulfonates - administration & dosage
Blotting, Western -
Cell Proliferation -
Cells, Cultured -
Colony-Forming Units Assay -
Drug Synergism -
Electrophoretic Mobility Shift Assay -
Female -
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Humans -
Immunoblotting -
Immunoenzyme Techniques -
Isoenzymes - metabolism
Isothiocyanates -
Luciferases - metabolism
Mice -
Mice, Nude -
NF-kappa B - genetics
NF-kappa B - metabolism
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Neovascularization, Pathologic -
Niacinamide - analogs & derivatives
Pancreatic Neoplasms - blood supply
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - pathology
Phenylurea Compounds -
Pyridines - administration & dosage
RNA, Messenger - genetics
RNA, Messenger - metabolism
Retinal Dehydrogenase -
Reverse Transcriptase Polymerase Chain Reaction -
Skin - cytology
Skin - drug effects
Skin - metabolism
Spheroids, Cellular - metabolism
Thiocyanates - administration & dosage
Xenograft Model Antitumor Assays -

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