Numerous cellular signaling pathways have been reported to be involved in the resistance for conventional cytotoxic drugs, although the overexpression of P-glycoprotein (P-gp), the membrane transporter, is one of the main mechanisms of multidrug resistance in cancer cells. Doxorubicin and paclitaxel, which have important role for the treatment of the various human malignancies, are the substrate of this transporter system. 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. PS341 and MG132 decreased the IC50 value of doxorubicin and paclitaxel in MCF7/ADR from 55.9±3.46 to 0.60±0.08 μM, and from 17.61±1.77 to 0.59±0.12 μM, respectively. Because that the IC50 value of doxorubicin and paclitaxel for parental MCF7 cells were about 0.42 μM and 0.83 μM, proteasome inhibitors reduced the degree of the drug resistance of MCF7/ADR cells. proteosome inhibitors . PS341 and MG132 decreased both protein and mRNA expression levels of P-gp on MCF7/ADR cells. Proteosome inhibitors also significantly decreased the MAP kinase and NF-kappaB activities, one of the possible signal transduction pathways related to the activation of mdr1. Western blot analysis revealed that 24hr exposure of proteasome inhibitors did remarkably decreased the expression levels of cytosolic NF-kappaB, ERK1/2, c-Jun and p-c-Jun in multidrug resistant MCF7/ADR. 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 though the suppression of P-gp. Several other proteins are supposed to be associated with the re-sensitization of the cells to conventional cytotoxic drugs. The interference with MAP kinase pathways and NF-kappaB activation, which have been reported to be associated with the regulation of P-gp, might be contributed to the re-sensitization brought by proteasome inhibitors.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]