Neoplasia (New York, N.Y.), 2011-03, Vol.13 (3), p.217-IN3
2011
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- Autor(en) / Beteiligte
- Titel
- Irinotecan Synergistically Enhances the Antiproliferative and Proapoptotic Effects of Axitinib In Vitro and Improves Its Anticancer Activity In Vivo
- Ist Teil von
- Neoplasia (New York, N.Y.), 2011-03, Vol.13 (3), p.217-IN3
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Aims: To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer. Methods: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer (MIAPaCa-2, Capan-1) cell lines exposed to SN-38, the active metabolite of irinotecan, axitinib, or their simultaneous combination for 72 hours. ERK1/2 and Akt phosphorylation, the vascular endothelial growth factor (VEGF), VEGF receptor-2, and thrombospondin-1 (TSP-1) concentration were measured by ELISAs. ATP7A and ABCG2 gene expression was performed with real-time polymerase chain reaction and SN-38 intracellular concentrations were measured by high-performance liquid chromatography. Capan-1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination. Results: A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib/SN-38 combination on endothelial and cancer cells. ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines. Axitinib and SN-38 combined treatment greatly inhibited the expression of the ATP7A and ABCG2 genes in endothelial and cancer cells, increasing the SN-38 intracellular concentration. Moreover, TSP-1 secretion was increased in cells treated with both drugs, whereas VEGFR-2 levels significantly decreased. In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization. Conclusions: In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells, suggesting a possible translation of this schedule into the clinics.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1476-5586eISSN: 1476-5586, 1522-8002DOI: 10.1593/neo.101334Titel-ID: cdi_doaj_primary_oai_doaj_org_article_4078a82823e84430ba68043b0887298e
- Format
- –
- Schlagworte
- Adenosine Triphosphatases - genetics, Adenosine Triphosphatases - metabolism, Animals, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Apoptosis - drug effects, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters - genetics, ATP-Binding Cassette Transporters - metabolism, Axitinib, Blotting, Western, Camptothecin - administration & dosage, Camptothecin - analogs & derivatives, Cation Transport Proteins - genetics, Cation Transport Proteins - metabolism, Cell Proliferation - drug effects, Cells, Cultured, Copper-transporting ATPases, Drug Synergism, Endothelium, Vascular - cytology, Endothelium, Vascular - drug effects, Enzyme-Linked Immunosorbent Assay, Humans, Imidazoles - administration & dosage, Immunoenzyme Techniques, Indazoles - administration & dosage, Irinotecan, Male, Mice, Mice, Nude, Mitogen-Activated Protein Kinase 1 - metabolism, Mitogen-Activated Protein Kinase 3 - metabolism, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, Neovascularization, Pathologic, Oncology, Pancreatic Neoplasms - blood supply, Pancreatic Neoplasms - pathology, Pancreatic Neoplasms - prevention & control, Phosphorylation, Proto-Oncogene Proteins c-akt - metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger - genetics, Thrombospondins - metabolism, Vascular Endothelial Growth Factor A - metabolism, Vascular Endothelial Growth Factor Receptor-2 - metabolism