MK-8669 Ridaforolimus As shown in FIG. 3, all compounds that have shown PXR-mediated Reporteraktivit t activate Pgp protein levels induced in the cells Pgp LS180. After analysis Pgp reporter both etoposide and carboplatin did not induce the expression of Pgp protein. To demonstrate that PXR plays an r In the up-regulation of Pgp Important PXR is spilled into LS180 cells. The cells . As shown in FIG. 3, the induction of protein is less than the Pgp signiWcantly knockdown PXR LS180 cells after the treatment with cytostatics in comparison to the control cells. However, Pgp induction was not completely Abolished constantly, probably because of the shock effect eYciency of 51%.
Rhodamine 123 accumulation tests to assess whether the induction of Pgp-mediated accumulation of PXR Pgp substrates Transportaktivit t AVects of Pgp has been using a rhodamine 123 enrichment test. After 48 h of treatment with cytostatics, the cells were exposed to rhodamine 123 in the absence or presence of the inhibitor of Pgp zosuquidar speciWc. The GDC-0449 ratio Ratio between the intracellular Xuorescence temperatures between rhodamine 123 in the presence and absence of zosuquidar is indicative of the Transportaktivit t in cells treated Pgp LS180. As shown in FIG. 4 rhodamine 123 is the accumulation of data PGP protein expression was low cellular Rhodamine Ren 123 accumulation of paclitaxel, docetaxel and Xutamide who have shown the expression of proteins observed to induce Pgp, w During etoposide and carboplatin not aVect rhodamine 123 accumulation.
However, is the Anh Ufung of rhodamine 123 in the cells that were treated with the periwinkle alkaloids, cyclophosphamide, ifosfamide and tamoxifen does not correspond Pgp protein expression. Evect the PXR activation on doxorubicin cytotoxicity t In order to investigate whether the activation of the PXR eYcacy t one Pgp substrate cytotoxic Evect the PXR activation on cytotoxicity Evaluated of doxorubicin in aVects LS180. Therefore prior doxorubicin exposure, LS180 cells were pretreated with the PXR agonists rifampicin prototype 10 M or 0. 1% DMSO in 48 h as shown. 5a, aVects rifampicin treatment the intracellular Re accumulation of doxorubicin. To determine whether decreased accumulation of doxorubicin also aVects eYcacy of this agent were rifampicin or L Solvent pretreated cells exposed to concentrations of doxorubicin diVerent.
As shown in FIG. 5b Lebensf Cell capacity after exposure doxorubicin signiWcantly h Ago pretreated cells with respect to rifampicin cells pretreated L Solvent. This indicates that the activation can also PXR activity t of Pgp substrates cytotoxic due to the decreased intracellular Re accumulation. Discussion The development of tuberculosis in response to the treatment of cancer is a big problem in the clinic. Since Pgp induction is one of the most important mechanisms acquired MDR, we investigated whether several k h Frequently used anticancer drugs Can the expression of Pgp by activation of PXR, a nuclear receptor, is to induce increasingly associated with acquired MDR.