Differential effect of phenothiazines on MRP1 and P-glycoprotein activity.

Background: Overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) or breast cancer resistance protein (BCRP) accounts for majority of cases of multidrug resistance (MDR) of cancer cells.

Methods: In the present work, the interactions of seven commercially available phenothiazine derivatives, known P-glycoprotein inhibitors, with this transporter and MRP1 were compared. By flow cytometry, it was shown that all the drugs increased the accumulation of rhodamine 123 in the P-gp-overexpressing lymphoma cell line L5178 MDR. On the other hand, phenothiazine derivatives stimulated MRP1-mediated efflux of fluorescent probe (BCPCF) out of human erythrocytes.

Results: In this way, these phenothiazine derivatives were identified as a group of atypical MDR modulators that differently interact with P-gp (as inhibitors) and MRP1 (as stimulators).

Conclusions: This observation clearly shows that the activity of all new modulators should be tested for their effects towards different ABC transporters as a standard procedure.