title: The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins.
abstract: Cisplatin is commonly used as a chemotherapeutic agent for hepatocellular carcinoma (HCC). However, it cannot satisfactorily improve the survival rate for patients with advanced HCC due to intrinsic or acquired drug resistance caused by multidrug resistance-associated proteins (MRPs). To clarify whether or not glycyrrhizin and lamivudine have modulator effects on HCC treated with cisplatin, we established a cisplatin-resistant Huh7 HCC cell line and analyzed the mRNA expression of MRPs in the resistant cells. The resistant cells showed 14.1-fold higher resistance to cisplatin, and they expressed higher levels of MRP2 (6.29-fold), MRP3 (3.2-fold), MRP4 (11.3-fold) and MRP5 (3.39-fold) mRNAs than the wild-type cells by using real-time PCR. However, MRP1, MDR1 and GST-pi mRNA were not induced. Compared with the treatment of the resistant cells with cisplatin only, co-treatment with cisplatin and glycyrrhizin or lamivudine significantly decreased the cell viability to 76.8% and 79.5%, respectively. Co-treatment with cisplatin and both glycyrrhizin and lamivudine further decreased the cell viability to 65.1%. Intracellular concentration of cisplatin in the resistant cells decreased to 36.4% of that of the wild-type cells while it increased to 47.7% or 48.4% when glycyrrhizin or lamivudine were added separately, or 60% when they were added together. Our findings indicate the following: i) high expression of MRP2, MRP3, MRP4 and MRP5 decreases cisplatin accumulation in cisplatin-resistant HCC cells and contributes to cisplatin resistance; ii) glycyrrhizin and/or lamivudine accumulate cisplatin in resistant cells by inhibiting the cisplatin efflux from the cells; and iii) glycyrrhizin and lamivudine both act as modulators and have the effect of reversing cisplatin resistance, and co-treatment with glycyrrhizin and lamivudine enhances modulator activity in reversing the cisplatin resistance.
authors.affiliation: Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Wakamatsu
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Nakahashi
authors.forename: Daisaku
authors.initials: D
authors.lastname: Hachimine
authors.forename: Toshihito
authors.initials: T
authors.lastname: Seki
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002945:Cisplatin; D019695:Glycyrrhizic Acid; D019259:Lamivudine; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C120809:ABCC5 protein, human; C421109:multidrug resistance-associated protein 1