title: Celecoxib antagonizes the cytotoxicity of oxaliplatin in human esophageal cancer cells by impairing the drug influx.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: kongyijk@126.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: pingchungu_2006@126.com.
authors.forename: Chunping
authors.initials: C
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: dersonzhong@163.com.
authors.forename: Desheng
authors.initials: D
authors.lastname: Zhong
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: 984623086@qq.com.
authors.forename: Xuyan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: 443853020@qq.com.
authors.forename: Qinghuan
authors.initials: Q
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: 380292021@qq.com.
authors.forename: Keng
authors.initials: K
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: 727582649@qq.com.
authors.forename: Tianrong
authors.initials: T
authors.lastname: Xun
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: yulezy@smu.edu.cn.
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address: liusw@smu.edu.cn.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008819:Mice, Nude; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; C491013:SLC22A2 protein, human; D000077150:Oxaliplatin; D000068579:Celecoxib
keywords: Celecoxib; Cyclooxygenase-2; Esophageal cancer; Organic cation transporters; Oxaliplatin