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...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 withNVP-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.展开更多
基金Supported by Grant No. 934000-258 from Novartis Oncology (to Wiedmann M)
文摘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 withNVP-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.
