title: Mechanisms of verapamil-enhanced chemosensitivity of gallbladder cancer             cells to platinum drugs: glutathione reduction and MRP1 downregulation.
abstract: Gallbladder cancer (GBC) is highly malignant with a low response rate after             chemotherapy and platinum drugs are currently prominent in the treatment of biliary             tract cancers. Therefore, the development of novel strategies to enhance the sensitivity             of GBC to platinum drugs is required. In the present study, we examined the effects             of verapamil, a classic chemosensitizer whose reported mechanisms of action include             inhibiting the transport function of P-glycoprotein (MDR1) or stimulating glutathione             (GSH) transport by multidrug resistance-related protein 1 (MRP1), in combination             with cisplatin (CDDP), carboplatin (CBP) or oxaliplatin on the GBC cell lines,             SGC996 and GBC-SD. Our results demonstrated that the co-treatment with verapamil             markedly enhanced the chemosensitivity of GBC cells in comparison with platinum             drug treatment alone. The mechanisms involved included GSH reduction and MRP1             downregulation. Verapamil/CDDP co-treatment inhibited tumor xenograft growth via             the downregulation of MRP1 expression. MRP1 was highly expressed in human GBC             tissue compared to non-tumorous gallbladder tissue. Our data demonstrate that             verapamil may be used as a safe chemosensitizer for platinum drugs in the treatment             of GBC. It functions by ROS and ATP-binding cassette transporter-related mechanisms.
authors.affiliation: Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, PR China.
authors.forename: Haolu
authors.initials: H
authors.lastname: Wang
authors.forename: Xinxing
authors.initials: X
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D016190:Carboplatin; D002945:Cisplatin; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014700:Verapamil; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1