Kong Yi, Gu Chunping, Zhong Desheng, Zhao Xuyan, Lin Qinghuan, Wang Keng, Xun Tianrong, Yu Le, Liu Shuwen
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Eur J Pharm Sci. 2016 Jan 1;81:137-48. doi: 10.1016/j.ejps.2015.10.009. Epub 2015 Oct 22.
It has been demonstrated that COX-2-selective inhibitor celecoxib shows synergy with oxaliplatin for suppressing tumor growth. However, the benefit of adding celecoxib to oxaliplatin-based regimen in human esophageal cancer is largely unknown. In the present study, we demonstrated that celecoxib antagonized oxaliplatin-induced cytotoxicity and apoptosis independent of COX-2 inhibition in human esophageal cancer cells. Celecoxib decreased cellular oxaliplatin accumulation and Pt-DNA adduction formation due to reduced drug influx. Celecoxib alone or combined with oxaliplatin substantially reduced the expression of organic cation transporter 2 (OCT2). To this end, OCT2 knockdown was sufficient to reduce oxaliplatin uptake, connecting OCT2 expression to oxaliplatin accumulation. Moreover, oxaliplatin combined with celecoxib also showed no beneficial effect when compared with monotherapy in esophageal cancer cell-xenografted nude mice. To conclude, our data provide evidence that the addition of celecoxib to oxaliplatin-containing regimens for patients with OCT2-expressing cancers should be cautious.
已证明COX-2选择性抑制剂塞来昔布与奥沙利铂在抑制肿瘤生长方面具有协同作用。然而，在人食管癌中，在基于奥沙利铂的方案中添加塞来昔布的益处很大程度上尚不清楚。在本研究中，我们证明塞来昔布在人食管癌细胞中拮抗奥沙利铂诱导的细胞毒性和凋亡，且与COX-2抑制无关。由于药物流入减少，塞来昔布降低了细胞内奥沙利铂的积累和铂-DNA加合物的形成。单独使用塞来昔布或与奥沙利铂联合使用可显著降低有机阳离子转运体2（OCT2）的表达。为此，敲低OCT2足以减少奥沙利铂的摄取，将OCT2表达与奥沙利铂积累联系起来。此外，与单药治疗相比，奥沙利铂联合塞来昔布在食管癌细胞异种移植裸鼠中也未显示出有益效果。总之，我们的数据提供了证据，对于表达OCT2的癌症患者，在含奥沙利铂的方案中添加塞来昔布应谨慎。
