In order to investigate the response of the pancreatic selleck chemicals llc cancer cell lines to direct inhibition of RAS/RAF/MAPK and PI3K/AKT signalling cascades as well as their dependency on these pathways, we determined the growth response of these cell lines to treatment with the PI3K inhibitor LY294002 and MAPKK/MEk inhibitor U0126. Both inhibitors were found to be less effective at inhibiting the growth of pancreatic cancer cell lines compared to IGF-IR inhibitor NVP-AEW541, with IC50s ranging from 2.3 ��M (Capan-1) to 13.7 ��M (PANC1) for MAPKK inhibitor and 5.5 ��M (AsPc-1) to 11.3 ��M (PANC1) for the PI3K inhibitor (Table 1). Interestingly, the most resistant cell lines to PI3K inhibition were also found to be resistant to anti-MAPKK treatment (Table 1, Figure 3B,C).
Cell-cycle distribution analyses We used flow cytometry in order to determine the effect of NVP-AEW541 (IC70 concentration) on the cell cycle distribution of the pancreatic cancer cell lines. We have reported recently that treatment with gemcitabine increased the percentage of cells in the sub-G1 and S phase while afatinib increased the proportion of cells in the sub-G1 and this was accompanied by a decrease in the population of cells in G0/G1 [19]. Similarly, an increase in the sub-G1 fraction, indicative of apoptosis, was observed in the majority of cell lines following NVP-AEW541 treatment and this was statistically significant in FA6, AsPC-1, PT45 and Capan-1 cells (Table 3). An increase in the percentage of cells in G0/G1 phase was demonstrated only in five out of the seven cell lines and this increase was statistically significant in BxPc3 and PANC1 (Table 3).
Table 3 Effect of NVP-AEW541 (IC70) on the cell cycle distribution of pancreatic cancer cell lines Effect of HER and IGF-IR ligands in the presence or absence of inhibitors on downstream cell signaling molecules First we determined the effect of EGF and IGF-I on the phosphorylation of AKT and MAPK in all pancreatic cancer cell lines included in this study and in all cell lines, with the Dacomitinib exception of FA6 cells, EGF primarily induced to the activation of MAPK while it had low or no effect on AKT phosphorylation. In contrast, IGF-I was more potent in inducing the activation of AKT, while having no or minimal effect on MAPK phosphorylation (Figure 5). Figure 5 Effect of IGF-I and EGF 20 nM (for 15 min) on downstream signaling pathways in all pancreatic cancer cell lines used in this study. Cells were grown to near-confluency in 10% FBS growth followed by 24 h incubation in 0.1% FBS growth medium at 37��C. … Next, we examined the effect of EGF, IGF-I, IGF-II, insulin and NRG1 on the activation of downstream signaling pathways in BxPc3 cell line in the presence or absence of afatinib, NVP-AEW541 or mAb ICR62 (Figure 6A).
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