TFPI-2 downregulates multidrug resistance protein in 5-FU-resistant human hepatocellular carcinoma BEL-7402/5-FU cells.

Tissue factor pathway inhibitor-2 (TFPI-2) is known to induce apoptosis and to suppress tumor metastasis in several types of cancer cells. However, there is little known about its reversal effect on chemoresistant tumor cells. This study investigated the effect of TFPI-2 in 5-fluorouracil (5-FU)-resistant human hepatocellular cancer BEL-7402/5-FU cells in vitro. We constructed TFPI-2 overexpression BEL-7402/5-FU cell lines and explored resistance index (RI) of 5-FU, function of the P-glycoprotein (P-gp) efflux pump, and the mRNA and protein expression of drug resistance gene, including multidrug resistance gene (MDR1), lung-resistance protein (LRP), multidrug resistance-associated protein (MRP1), glutathione-S-transferase-π (GST-π), excision repair cross-complementing gene 1 (ERCC1), and p38 phosphorylation. We found that TFPI-2 improved the RI of 5-FU and inhibited P-gp function. Western blotting and real-time PCR revealed that TFPI-2 also decreased mRNA and protein expression of MDR1, LRP, MRP1, GST-π, and ERCC1, whereas p38 phosphorylation was increased. We considered that TFPI-2 reduces 5-FU resistance in BEL-7402/5-FU cells, and the mechanism appears to involve p38-mediated downregulation of drug resistance gene expression such as MDR1, LRP, MRP1, GST-π, and ERCC1.

Lu F ，Hou YQ ，Song Y ，Yuan ZJ ... -  《-》

Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells.

Jiao JW ，Wen F 《-》

Reversal of P-glycoprotein-mediated multidrug resistance of human hepatic cancer cells by Astragaloside II.

Chemoresistance is the main obstacle encountered in cancer treatment and is frequently associated with multidrug resistance (MDR). Astragaloside is a saponin which is widely used in traditional Chinese medicine. It has been reported that Astragaloside has antitumour effects on hepatocellular carcinoma Bel-7402 cells in vitro and in vivo. The purpose of this study was to examine the effects of Astragaloside II on the reversal of MDR and its molecular mechanism in vitro. In this study, Bel-7402 and Bel-7402/FU cell lines were used as the experimental model. Drug sensitivity was determined using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, accumulation and efflux of Rh123 were analyzed by flow cytometer, the mRNA level of mdr1 was determined by RT-PCR and the protein levels of P-glycoprotein (P-gp) and mitogen-activated protein kinase were determined by Western blot. Astragaloside II (0.08 mg/ml) showed strong potency to increase 5-fluorouracil cytotoxicity toward 5-fluorouracil-resistant human hepatic cancer cells Bel-7402/FU. The mechanism of Astragaloside II on P-gp-mediated MDR demonstrated that Astragaloside II significantly increased the intracellular accumulation of rhodamine 123 via inhibition of P-gp transport function. Based on the analysis of P-gp and mdr1 gene expression using Western blot and RT-PCR, the results revealed that Astragaloside II could downregulate the expression of the P-gp and mdr1 gene. In addition, Astragaloside II suppressed phosphorylation of extracellular signal regulated kinase 1/2, p38 and c-Jun N-terminal kinase. The results suggested that Astragaloside II is a potent MDR reversal agent and may be a potential adjunctive agent for hepatic cancer chemotherapy.

Huang C ，Xu D ，Xia Q ，Wang P ，Rong C ，Su Y ... -  《-》

Reversal effect of tyroservatide (YSV) tripeptide on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU.

Shi LX ，Ma R ，Lu R ，Xu Q ，Zhu ZF ，Wang L ，Zhou CL ，Li XL ，Zhang HL ，Yao Z ... -  《-》

MiR-27a modulates the MDR1/P-glycoprotein expression by inhibiting FZD7/β-catenin pathway in hepatocellular carcinoma cells.

Chemotherapy has been widely used to treat cancer, however, the appearance of multiple drug resistance (MDR) in cancer patients is regarded as a major clinical obstacle to successful chemotherapy. MicroRNAs (miRNAs) are evolutionary conserved small RNAs that regulate gene expression at the post-transcriptional level and have been shown to regulate cell differentiation, development, proliferation and apoptosis. Nevertheless, the involvement of miRNAs and their roles in the development of MDR in liver cancer are not fully understood. Our study found that the expression of miR-27a was down-regulated in the multidrug-resistant hepatocellular carcinoma cell line BEL-7402/5-fluorouracil (BEL/5-FU) compared with its parental BEL-7402 cell line, while the MDR1/P-glycoprotein expression was elevated. Overexpression of miR-27a by transfecting with miR-27a mimics in the BEL/5-FU cells could reduce the MDR1/P-glycoprotein and β-catenin expressions, enhance the sensitivity of these cells to 5-fluorouracil and 5-fluorouracil-induced apoptosis. Moreover, up-regulation of miR-27a did not decrease the FZD7 mRNA level, but significantly reduce its protein expression in BEL/5-FU cells. It was also confirmed that reduction of FZD7 by RNA interference induced inhibitory effects on the expression of MDR1/P-glycoprotein and β-catenin, similar to miR-27a. Taken together, our findings suggest that miR-27a could function as a novel regulator to reverse MDR in hepatocellular carcinoma cells by inhibiting the FZD7/β-catenin pathway.

Chen Z ，Ma T ，Huang C ，Zhang L ，Lv X ，Xu T ，Hu T ，Li J ... -  《-》