Treatment of biliary tract cancer with NVP-AEW541: mechanisms of action and resistance
| Autor: | Jana Lorenz, Marcus Wiedmann, Samuel J. Wolf, Joachim Mössner |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Cell cycle checkpoint Antineoplastic Agents Biology Deoxycytidine Receptor IGF Type 1 Internal medicine Cell Line Tumor medicine Humans Pyrroles Receptor Autocrine signalling Protein kinase B Cell Proliferation Cell growth Kinase Pteridines Gastroenterology Drug Synergism General Medicine Gemcitabine Endocrinology Biliary Tract Neoplasms Pyrimidines Cell culture Drug Resistance Neoplasm Cancer research Drug Therapy Combination Gallbladder Neoplasms Original Article Fluorouracil Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | World journal of gastroenterology. 16(2) |
| ISSN: | 2219-2840 |
| Popis: | AIM: To investigate in vitro treatment with NVPAEW541, a small molecule inhibitor of insulin-like growth factor-1 receptor (IGF-1R), in biliary tract cancer (BTC), since this disease is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. METHODS: Cell growth inhibition by NVP-AEW541 was studied in vitro in 7 human BTC cell lines by automated cell counting. In addition, the anti-tumoral mechanism of NVP-AEW541 was studied by Western blotting, cell cycle analysis and reverse transcription-polymerase chain reaction (RT-PCR). Anti-tumoral drug effect in combination with gemcitabine, 5-fluorouracil (5-FU) and Polo-like kinase 1 inhibitor BI2536 was also studied. RESULTS: In vitro treatment with NVP-AEW541 suppressed growth in all human BTC cell lines, however response was lower in gallbladder cancer. Treatment with NVP-AEW541 was associated with dephosphorylation of IGF-1R and AKT. In contrast, phosphorylation of p42/p44 and Stat3 and expression of Bcl-xL were inconsistently downregulated. In addition, treated cells showed cell cycle arrest at the G1/S-checkpoint and an increase in sub-G1 peak. Moreover, IGF-1R and its ligands IGF-1 and IGF-2 were co-expressed in RT-PCR, suggesting an autocrine loop of tumor cell activation. Combined with gemcitabine, NVP-AEW541 exerted synergistic effects, particularly at low concentrations, while effects of combination with 5-FU or BI 2536 were only additive. CONCLUSION: Our findings suggest that NVP-AEW541 is active against BTC in vitro and potentiates the efficacy of gemcitabine. |
| Databáze: | OpenAIRE |
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