Attenuating effect of PS341 for MDR1 in multidrug resistant breast cancer

Abstract

2087 Background: Over-expression of P-gp has been associated with the resistance to a wide range of anti-cancer drugs. Doxorubicin and paclitaxel are substrate of this transporter system and have important role for the various human malignancies, especially in the treatment of breast cancer. Here we demonstrate that proteasome inhibitors could remarkably enhance drug sensitivities for MDR1 overexpressed multidrug resistant breast cancer and analyzed the estimated pathways involved in it Methods: 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. And two proteasome inhibitors;PS341 and MG132 were used as treatment drugs. Results: PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9±3.46 to 0.60±0.08 uM, and from 17.61±1.77 to 0.59±0.12 uM. The IC50 value of sensitive cells for doxorubicin and paclitaxel were about 0.42 uM and 0.83 uM. The effect of PS341 and MG132 on MCF7/ADR cells was associated with significantly decreased both protein and gene levels of P-gp expression. Moreover, regard with the expression of possible signal transduction pathways of MAP kinase related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did remarkably decreased levels of cytosolic NF-kappaB, ERK1/2, c-Jun and p-c-Jun. Conclusions: 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 re-sensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related re-sensitization. And influence with signal transduction pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the re-sensitization brought by proteasome inhibitors. No significant financial relationships to disclose.