Identification of P-Glycoprotein and Transport Mechanism of Paclitaxel in Syncytiotrophoblast Cells

Abstract

When chemotherapy is administered during pregnancy, it is important to consider the fetus chemotherapy exposure, because it may lead to fetal consequences. Paclitaxel has become widely used in the metastatic and adjuvant settings for woman with cancer including breast and ovarian cancer. Therefore, we attempted to clarify the transport mechanisms of paclitaxel through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of paclitaxel was time- and temperature-dependent. Paclitaxel was eliminated about 50% from the cells within 30 min. The uptake of paclitaxel was saturable with Km of 168 μM and 371 μM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. [3H]Paclitaxel uptake was markedly inhibited by cyclosporine and verapamil, well-known substrates of P-glycoprotein (P-gp) transporter. However, several MRP substrates and organic anions had no effect on [3H]paclitaxel uptake in TR-TBT cells. These results suggest that P-gp may be involved in paclitaxel transport at the placenta. TR-TBT cells expressed mRNA of P-gp. These findings are important for therapy of breast and ovarian cancer of pregnant women, and should be useful data in elucidating teratogenicity of paclitaxel during pregnancy.

Human amniotic mesenchymal stromal cells (hAMSCs) as potential vehicles for drug delivery in cancer therapy: an in vitro study

“…Over the last few years, several studies have been performed to better understand the role that placenta plays in distributing pharmacological agents within the maternal and fetal compartments [ 31 ] and the presence of several drug efflux proteins in placenta has been demonstrated [ 32 ]. For example, the expression of the breast cancer resistant protein (BCRP) has been previously described [ 33 ], while other authors confirmed the presence of P-gp in syncytiotrophoblast cells [ 34 , 35 ]. It is interesting to note that, despite its presence, P-gp protein does not seem to have a role in PTX transport in human placenta [ 36 ].…”

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

“…The uptake of paclitaxel was inhibited by known P-gp substrates such as verapamil and cyclosporine, but the MRP substrates displayed no effect. The studies showed that mRNA of P-gp was expressed in these cell lines and that P-gp was involved in the transport of paclitaxel (90). …”

Human Olfactory Bulb Neural Stem Cells (Hu-OBNSCs) Can Be Loaded with Paclitaxel and Used to Inhibit Glioblastoma Cell Growth

“…The drug resistance of some cancer cells (such as breast cancer) has been attributed to their ability to modulate/upregulate the expression of breast cancer resistant protein (BCRP) [34]. Moreover, the presence of the drug-efflux P-gp protein has been demonstrated in placental syncytiotrophoblast cells as well [35,36]. Whether or not the drug-efflux P-gp protein (or a similar protein) is implicated in the marked resistance of Hu-OBNSCs to PTX is a matter that needs further investigation, because previous studies have asserted that despite its expression in human placental cells, P-gp protein does not seem to have a role in PTX transport [37].…”