Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
J Surg Res. 2013 Sep;184(1):605-12. doi: 10.1016/j.jss.2013.06.003. Epub 2013 Jun 25.
Gemcitabine is an effective chemotherapeutic agent for advanced gallbladder cancer. However, chemoresistance attributable to gemcitabine-induced nuclear factor-κB (NF-κB) activation has been reported. We previously reported that nafamostat mesylate inhibited NF-κB activation and induced apoptosis in pancreatic cancer. Therefore, we hypothesized that nafamostat mesylate inhibits gemcitabine-induced NF-κB activation and enhances apoptosis induced by gemcitabine in gallbladder cancer.
In vitro, we assessed NF-κB activation of a gallbladder cancer cell line (NOZ) treated with nafamostat mesylate, gemcitabine, or a combination of both. In vivo, we established a xenograft gallbladder cancer model in mice by subcutaneous injection of NOZ cells. Five weeks after implantation, the animals were treated with nafamostat mesylate three times a week in the nafamostat mesylate group, with gemcitabine once a week in the gemcitabine group, or with a combination of nafamostat mesylate three times a week and gemcitabine once a week in the combination group, respectively. In the control group, only the vehicle of gemcitabine and nafamostat mesylate was injected at the same time course.
In the combination group, NF-κB activation was inhibited and apoptosis was enhanced compared with gemcitabine alone in vitro and vivo. Tumor growth in the combination group was significantly slower than that in the gemcitabine group (P < 0.001). At the end of the study, the tumor weight and volume in the combination group were significantly lower than those in the gemcitabine group (P = 0.039 and 0.028, respectively).
Combination chemotherapy of gemcitabine with nafamostat mesylate enhances the anti-tumor effect against xenograft gallbladder cancer model in mice.
吉西他滨是晚期胆囊癌的有效化疗药物。然而，已经报道了吉西他滨诱导的核因子-κB（NF-κB）激活导致的化疗耐药性。我们之前报道过甲磺酸萘莫司他抑制 NF-κB 激活并诱导胰腺癌凋亡。因此，我们假设甲磺酸萘莫司他抑制吉西他滨诱导的 NF-κB 激活，并增强吉西他滨诱导的胆囊癌细胞凋亡。
在体外，我们评估了甲磺酸萘莫司他、吉西他滨或两者联合处理的胆囊癌细胞系（NOZ）的 NF-κB 激活。在体内，我们通过皮下注射 NOZ 细胞在小鼠中建立异种移植胆囊癌模型。植入后 5 周，甲磺酸萘莫司他组每周三次、吉西他滨组每周一次、联合组每周三次甲磺酸萘莫司他联合每周一次吉西他滨分别进行治疗。在对照组中，仅在相同时间点注射吉西他滨和甲磺酸萘莫司他的载体。
在体外和体内，联合组与单独使用吉西他滨相比，NF-κB 激活受到抑制，凋亡增强。联合组的肿瘤生长速度明显慢于吉西他滨组（P<0.001）。研究结束时，联合组的肿瘤重量和体积明显低于吉西他滨组（P=0.039 和 0.028）。
吉西他滨联合甲磺酸萘莫司他化疗增强了对异种移植胆囊癌细胞模型的抗肿瘤作用。
