Treatment of biliary tract cancer with NVP-AEW541: mechanisms of action and resistance.
OBJECTIVE
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.


CONCLUSIONS
Our findings suggest that NVP-AEW541 is active against BTC in vitro and potentiates the efficacy of gemcitabine.
Wolf
Samuel
S
Department of Internal Medicine II, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
Lorenz
Jana
J
Mössner
Joachim
J
Wiedmann
Marcus
M
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000627:therapeutic use; D005706:Gallbladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011621:Pteridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
D000970:Antineoplastic Agents; C518477:BI 2536; C501177:NVP-AEW541; D011621:Pteridines; D011743:Pyrimidines; D011758:Pyrroles; D003841:Deoxycytidine; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil; D000093542:Gemcitabine