Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance

Abstract

Numerous signaling pathways were reported to be involved in the resistance for conventional cytotoxic drugs, although one of the main reasons is the overexpression of P-glycoprotein (P-gp) in multidrug resistant cancer cells. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. Doxorubicin and paclitaxel are substrates of this transporter system and have an important role for the various human malignancies. In the present study, drug-sensitive MCF7 and multidrug resistant MCF7/ADR (characterized by overexpression of P-gp) human breast cancer cell lines were used as an experimental model. We have found that PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance (MDR) in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9 6 3.46 to 0.60 6 0.08 lM, and from 17.61 6 1.77 to 0.59 6 0.12 lM, respectively. The IC50 values of sensitive cells for doxorubicin and paclitaxel were about 0.42 and 0.83 lM, respectively. The effect of PS341 and MG132 on MCF7/ADR cells was associated with a significant decrease in both protein and gene levels of P-gp expression. Moreover, with regard to the expression of possible signal transduction pathways of mitogen-activated protein kinase (MAPK) related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24 hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did change the levels of DNA binding activity of nuclear factor-kappaB (NFkappaB), pERK1/2, c-Jun, and p-c-Jun. In conclusion, we could remark that proteasome inhibitors (especially PS341) attenuate the resistance of MCF7/ADR cells for P-gp substrate drugs of doxorubicin and paclitaxel. Several proteins are supposed to be associated with the resensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related resensitization. And influence with MAPK pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the resensitization brought by proteasome inhibitors. ' 2005 Wiley-Liss, Inc.

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

“…12,13 In this study, the REIC/Dkk-3 overexpression in MCF7/ADR cells caused the c-Jun activation and P-glycoprotein downregulation in a JNK-dependent manner. Using the other adriamycinresistant cancer cell line, bladder cancer KK47/ADM, we also confirmed the overexpression of REIC/Dkk-3 because of Ad-REIC treatment to downregulate the P-glycoprotein expression in a JHK and c-Jun-dependent manner while also improving drug resistance (data not shown).…”

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

“…Bortezomib and MG-132, proteasome inhibitors, reportedly reduced the degree of the MDR in MCF-7/DOX cells, 24) and MG-132 apparently reversed the MDR of gastric cancer by inhibiting P-gp. 25) These findings suggest that proteasome inhibitors attenuate the expression of P-gp and induce 27) In the RPMI-8226/TP-110 cells, our results clearly indicate that a proteasome inhibitor, TP-110, is the substrate of ABCB1 (P-gp).…”

The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State

“…Recent studies have shown that proteasome inhibition leads to an activation of the JNK pathway (16,52,80). As the JNK pathway is activated upon influenza virus infection and it is involved in antiviral signaling, whether PS-341 affects this signaling pathway in A549 cells has been investigated (44,45,48).…”