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.
Wesołowska
Olga
O
Department of Biophysics, Wrocław Medical University, Wrocław, Poland. olawes@biofiz.am.wroc.pl
Molnar
Joseph
J
Ocsovszki
Imre
I
Michalak
Krystyna
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007940:Leukemia L5178 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010640:Phenothiazines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010640:Phenothiazines; D020112:Rhodamine 123; C421109:multidrug resistance-associated protein 1