CAJ | 학술논문

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,howeve rresponse was lower in gallbladder cancer. Treatment with NVP-AEW 541 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-AEW541is active against BTC in vitro and potentiates the efficacy of gemcitabine.