Kombinierte Inhibition von Raf-Kinase und IGF-IR blockiert multiple pro-angiogenetische Signalwege und steigert die Chemosensitivität humaner Pankreaskarzinomzellen
| Autor: | B. Kaufmann, Sa Lang, Philipp Schachtschneider, O. Stöltzing, C. Zülke, Christian Moser, HJ Schlitt, Edward K. Geissler |
|---|---|
| Jazyk: | němčina |
| Rok vydání: | 2007 |
| Předmět: | |
| Zdroj: | 124. Kongress der Deutschen Gesellschaft für Chirurgie; 20070501-20070504; München; DOC07dgch7110 /20071001/ Chirurgisches Forum 2007 ISBN: 9783540711223 |
| Popis: | Overexpression of IGF-I/IGF-IR and activation of Ras/Raf signaling cascades have been implicated in angiogenesis and progression of human pancreatic cancer. Both signaling systems may up-regulate VEGF expression and mediate anti-apoptotic effects, which also promote mechanisms of chemoresistance. We therefore propose that selective blockade of IGF-IR and Raf-signaling in human pancreatic cancer cells impairs pro-angiogenic signaling, reduces VEGF and improves sensitivity to chemotherapeutic agents. Studies were performed with L3.6pl and HPAF-II human pancreatic cancer cell lines. Specific inhibitors to IGF-IR (AEW541) and Raf-kinase (AAL881) were used for experiments. Effects of specific inhibition by either compound alone, or in combination of both, on constitutive and IGF-I induced activation of signaling pathways, were assessed by Western Blots. Impact of AEW541 and/or AAL881 on VEGF secretion was determined by ELISA. Cancer cell motility was tested by in vitro assays using modified Boyden chambers. Cytotoxic effects of AEW541 and/or AAL881 in combination with Oxaliplatin were assessed by MTTs and cell death assays. In vitro, AEW541 significantly reduced constitutive and IGF-I induced phosphorylation of IGF-IR, IRS-1, MAPK/Erk1/2 and PI-3K/Akt as well as activation of the transcription factor STAT3. Combination of AEW541 and AAL881 led to significant inhibition of VEGF secretion as determined by ELISA. Furthermore, tumor cell motility in vitro was markedly impaired by combined therapy. MTT and cell death assays revealed modest cytotoxic effects of AEW541 or AAL881 alone. This effect was significantly improved by combined low-dose therapy of AEW541 and AAL881. In addition, combination therapy enhanced cytotoxic effects of Oxaliplatin. In conclusion, combined inhibition of IGF-IR and Ras/Raf-signaling cascades impairs pro-angiogenic signaling in human pancreatic cancer cells and harbors the potential to improve susceptibility to chemotherapeutic agents. Thus, targeting IGF-IR and Raf could be a promising strategy for molecular targeted therapy of pancreatic cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|