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-π 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.

Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer

“…Interestingly, another dCK substrate, lamivudine or 3TC, was also recently shown to inhibit multidrug resistance-associated proteins and enhance the effects of conventional chemotherapy. 48 Finally, BVdU is more lipophilic than GCV, 21 and is better suited for applications targeted to brain tumors that rely on significant passage of the therapeutic prodrug across the blood --brain barrier.…”

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

“…Chemoresistance of hepatocellular carcinoma can be achieved by upregulation of the drug transporter family known as the adenosine triphosphate-binding cassette (ABC) transporters such as ABCB1, ABCC1, ABCC2, and ABCC3 (8)(9)(10)(11), leading to increment of drugs efflux system to remove drugs out of cells. High levels of MRP2, MRP3, MRP4, and MRP5 genes have been found in an acquired cisplatinresistant hepatocellular carcinoma cell line (12). Moreover, recent findings have suggested that liver cancer stem cells contribute to chemoresistance of hepatocellular carcinoma.…”

Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma

“…Of several identified ABC transporters, MRP2 is the principal cisplatin transporter (7)(8)(9). There is a paucity of clinical data regarding any relationship between MRP2 expression and tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy prior to hepatectomy for HCC.…”

“…In vitro experiments have shown that elevated expression of MRP2 decreases cisplatin accumulation in HCC cells and contributes to cisplatin resistance (9). Transfection of MRP2 antisense cDNA into a human hepatoma cell line decreased the MRP2 protein level and increased sensitivity to cisplatin (10).…”

“…MRP2 is one of the major transporters of cisplatin (7)(8)(9). In vitro experiments have shown that elevated expression of MRP2 decreases cisplatin accumulation in HCC cells and contributes to cisplatin resistance (9).…”