The roles of four multi-drug resistance proteins in hepatocellular carcinoma multidrug resistance

Abstract

The roles of multi-drug resistance protein 1 (MDR1), multi-drug resistance related protein 1 (MRP1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) in the multi-drug resistance (MDR) of hepatocellular carcinoma (HCC) were studied. By exposing HepG2 cell line to progressively increased concentrations of adriamycin (ADM), HepG2 multi-drug resistant subline (HepG2/ADM) was induced. The MDR index of HepG2/ADM was detected by using MTT. The expressions of the four MDR proteins in the three cell lines (L02, HepG2, HepG2/ADM) were investigated at mRNA and protein levels by real-time RT-PCR and Western blot respectively. Our results showed that when the ADM concentration was under 100 microg/L, HepG2 could easily be induced to be drug-resistant. The IC(50) of the HepG2/ADM to ADM was 282 times that of HepG2. The expression of MDR1 and BCRP mRNA in HepG2/ADM cells were 400 and 9 times that of HepG2 cells respectively while there was no difference in the mRNA expressions of MRP1 and LRP. There was no difference between HepG2 and L02 cells in the mRNA expressions of the four genes. At the protein level, the expressions of MDR1, BCRP and LRP but MRP1 in HepG2/ADM were significantly higher than those of HepG2 and L02. Between HepG2 and L02, there was no difference in the expressions of four genes at the protein level. HepG2/ADM is a good model for the study of MDR. The four genes are probably the normally expressed gene in liver. The expressions of MDR1 and BCRP could be up-regulated by anti-cancer agents in vitro. The MDR of HCC was mainly due to the up-regulation of MDR1 and BCRP but MRP1 and LRP. These findings suggest they may serve as targets for the reversal of MDR of HCC.

Characterization and Resistance Mechanisms of A 5-fluorouracil-resistant Hepatocellular Carcinoma Cell Line

“…It has been suggested that overexpression of P-gp but not MRP1 mainly contributes to the MDR of SMMC-7721/ADM cells (Yan et al, 2010). The upregulation of P-gp and BCRP but not MRP1 and LRP are involved in the MDR of HepG2/ADM cells (Li et al, 2007;Sun et al, 2010). Overexpression of P-gp is also a predominant mechanism to explain the MDR in a taxol-resistant cell line, QGY-TR50 (Zhou et al, 2001).…”

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment in�vitro

“…As a potential explanation for this increased chemotherapy resistance, significantly increased expression levels of MDR1 (ABCB1) and MRP1 (ABCC1) were found; these genes are known to contribute to multidrug resistance in HCC (12)(13)(14)(15)17,18,20). MRP1, which is overexpressed in HCC (39), performs an important role in the intrinsic multidrug resistance of HCC and is also associated with an aggressive tumor phenotype and has been suggested to indicate a progenitor cell origin (18).…”

“…While a large proportion of doxorubicin is eliminated from the body unchanged, the main pathway of doxorubicin metabolism is two-electron reduction by cytosolic reductases, of which carbonyl reductase 1 is the most important in the liver (10). However, doxorubicin resistance in HCC cells is predominantly associated with the expression of adenosine triphosphate-binding cassette (ABC) transporters such as ABCB1 (multi-drug resistance gene; MDR1) or ABCC1 (multidrug resistance-associated protein 1; MRP1) (10,(12)(13)(14)(15)(16)(17)(18)(19).…”

The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma

“…After 48 hours' incubation, the cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, as described in an earlier publication. 31 Following this, the cell survival curves were drawn, from which the half maximal inhibitory concentration of the three agents was calculated.…”

“…The subsequent reverse transcription real-time polymerase chain reaction analyses were performed according to the procedure outlined in a previous study. 31 The primers were synthesized by Biocolors (Shanghai, People's Republic of China), with the oligonucleotide sequences as shown in Table 1.…”