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.