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Počet príspevkov : 542 Registration date : 18.12.2013
| Predmet: Results were expressed as fold induction of pCCD1 Luc activity in CNE1 cells, w Po február 10, 2014 9:46 am | |
| MCF 7 BCRP cells were found to overexpress BCRP and they showed ARN-509 分子量 significantly higher resistances to SN 38 and topotecan, which are both BCRP substrate drugs, than the corresponding parental cells, MCF 7 BCRP cells also acquired slightly more resistance to the PI3K inhibitors, but the degrees of resistance did not seem to be significant con sidering the degrees of resistance against anticancer drugs. LY294002 significantly enhanced cytotoxicities of SN 38 and topotecan on MCF 7 BCRP cells in a dose dependent manner, while it little affected the cytotoxici ties on MCF 7 cells, On the other hand, wortmannin and PI 103 did not show any significant re versing effects of BCRP mediated drug resistances in the cells, LY294002 treat ment reversed BCRP mediated multidrug resistance, but total BCRP levels or cell surface BCRP levels in MCF 7 BCRP cells were not affected by the treatment with up to 5 or 2 uM of LY294002, re spectively.<br><br> Effects of LY294002 on cellular accumulation of topotecan were then evaluated by flow cytometric analysis. Cellular topotecan uptake was remarkable in the parental MCF 7 cells but AUY922 分子量 not in the MCF 7 BCRP cells in the absence of LY294002, LY294002 treatment at the concentrations of 10 20 uM clearly demonstrated increased cellular topotecan uptake in a dose dependent manner in the medium containing 40 uM of topotecan, The effects were weaker than those of gefitinib but were stronger than estrone in this situation, This surprising result suggested that trafficking problem was not a main rea son for the loss of BCRP function mediated by LY294002.<br><br> Fluorescence immunohistochemistry con firmed that MCF 7 BCRP cells treated with LY294002 expressed BCRP mainly on the plasma membrane in this experimental setting, For the past Alvocidib Flavopiridol decade, PI3K Akt inhibitors have been known to cause more favorable outcomes when co administered with usual anticancer drugs. Deregulation of drug transporters is one of the postulated mechan isms. It had been reported that inhibition of the PI3K Akt pathway modulated BCRP mediated drug transport via BCRP translocation in SP cells in the bone marrow and glioma stem like cells. It was also reported that inhibition of the PI3K Akt pathway resulted in BCRP translocation in renal polarized cells, However, effects of the PI3K Akt inhibitors on BCRP function were found to be considerably different in BCRP transfected MCF 7 cells.<br><br> LY294002 did not affect cel lular BCRP distribution in the cancer cell line but exerted inhibitory effects on BCRP mediated topotecan efflux. Thus, LY294002 demonstrated BCRP inhibitory effects different from those observed in the previous studies. Then, two possible explanations were postu lated to explain the results. The first one was the dif ference of cell characters between stem cells and non stem cells. Regulation of subcellular BCRP distri bution by the PI3K Akt pathway might be specific to a subset of cells such as stem stem like cells. It is known that the PI3K Akt signaling pathway is acti vated and plays a role in the maintenance of pluripo tency and viability of stem cells . BCRP is expressed on the cell surface of pluripotent stem cells but becomes downregulated with cell maturation. | |
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