Z-360 Suppresses Tumor Growth in MIA PaCa-2-bearing Mice via Inhibition of Gastrin-induced Anti-Apoptotic Effects

Background/aim: The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a Gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model.

Materials and methods: The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on Apoptosis in the model was examined by TUNEL staining and Real-Time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by Caspase-3/7 activity.

Results: In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as Survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited Apoptosis in vitro and Z-360 dose-dependently abrogated this effect.

Conclusion: These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.

MiaPaCa-2; Pancreatic cancer; Z-360; apoptosis; cholecystokinin-2 receptor; gastrin; gemcitabine; xenograft.