Treatment of biliary tract cancer with NVP-AEW541: Mechanisms of action and resistance
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Wolf, Samuel, Lorenz, Jana, Mössner, Joachim and Wiedmann, Marcus (2010) Treatment of biliary tract cancer with NVP-AEW541: Mechanisms of action and resistance. World Journal of Gastroenterology, 16 (2). pp. 156-166. ISSN 1007-9327
Abstract
AIM: To investigate in vitro treatment with NVP-AEW541,
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.
| Item Type: | Article |
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| Additional Information: | Archiving status unclear? |
| Keywords: | Tyrosine kinase inhibitor; Cholangiocarcinoma; Gemcitabine; NVP-AEW541 |
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| Date Deposited: | 13 Oct 2015 13:16 |
| Last Modified: | 13 Oct 2015 13:16 |
| URI: | https://oak.novartis.com/id/eprint/2545 |