Shiomi Yoshihiro, Yoshimura Makoto, Kuki Kazumasa, Hori Yuko, Tanaka Takao
Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Kumagaya, Japan
Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Kumagaya, Japan.
Anticancer Res. 2017 Aug;37(8):4127-4137. doi: 10.21873/anticanres.11800.
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.
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.
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.
These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.
背景/目的：本研究旨在评估胃泌素/胆囊收缩素-2受体（CCK2R）拮抗剂Z-360在MIA PaCa-2细胞和皮下异种移植小鼠模型中的抗肿瘤机制。
使用MIA PaCa-2异种移植模型监测Z-360和/或吉西他滨的抗肿瘤作用。通过TUNEL染色和实时PCR分析检测Z-360对模型中细胞凋亡的影响，并且还通过caspase-3/7活性评估Z-360对稳定表达人CCK2R的MIA PaCa-2细胞的作用。
在该异种移植模型中，Z-360显著降低肿瘤重量，增加TUNEL阳性细胞，并抑制抗凋亡因子如生存素、XIAP和Mcl-1的表达，并且Z-360与吉西他滨联合使用的这些效果更有效。此外，胃泌素-17和胃泌素-34在体外抑制细胞凋亡，而Z-360剂量依赖性地消除这种作用。
这些结果表明，Z-360通过阻断CCK2R减少抗凋亡因子发挥抗肿瘤作用。
