title: Differential effect of phenothiazines on MRP1 and P-glycoprotein activity.
abstract: 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.
authors.affiliation: Department of Biophysics, Wrocław Medical University, Wrocław, Poland. olawes@biofiz.am.wroc.pl
authors.forename: Olga
authors.initials: O
authors.lastname: Wesołowska
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.forename: Krystyna
authors.initials: K
authors.lastname: Michalak
mesh_terms: 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
chemical_list: 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