Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma

Background. Malignant mesothelioma is a devastating disease with a poor prognosis. Recent data have shown that insulin-like growth factor-1 receptor (IGF-1R) may play a role in oncogenic signaling. Our aim was to evaluate the effect of a novel IGF-1R inhibitor, NVP-AEW541, on cell growth and IGF associated pathways. Methods. Malignant mesothelioma cell lines, H2373 and H2461, previously shown to activate the IGF pathway were grown in culture. The adherent cells, initially plated at 5 x 105 cells/plate, were treated for 72 hours, in triplicate, with varying concentration of NVP-AEW541 (0, 1, 5, 10, 20, and 50 mu M). Viable cells were counted every 24 hours. Additionally, separate cultures in serum-free medium were treated with NVP-AEW541, then stimulated with IGF and lysates collected for immunoblot analysis. Results. In both cell lines, 0, 1, 5, and 10 mu M showed an inhibitory or static effect, while 20 and 50 mu M were cidal. Immunoblot analysis demonstrated that phosphorylation of IGF-1R was inhibited by NVP-AEW541 at higher concentration. Phosphorylation of mitogen-activated protein kinase and Akt, downstream IGF pathway mediators, were also shown to be repressed by drug treatment. Conclusions. NVP-AEW541 has a concentration-dependent inhibitory effect on mesothelioma cells in culture. NVP-AEW541 acts by inhibition of IGF-1R phosphorylation. Inhibition effects phosphorylation of downstream mediators in a dose-dependent fashion. Inhibition of the IGF pathway decreases viability of mesothelioma cell culture. Further evaluation of NVP-AEW541, and other selective IGF-1R inhibitors, may play an important role in multimodal treatment of malignant mesothelioma.