Differential effect of phenothiazines on MRP1 and P-glycoprotein activity

Olga Wesołowska, Joseph Molnar, Imre Ocsovszki, Krystyna Michalak

Research output: Contribution to journalArticle

21 Citations (Scopus)

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. Materials and Methods: In the present work, the interactions of seven commercially available phenothiazine derivatives, known P-glycoprotein inhibitors, with this transporter and MRPl 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). Conclusion: 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.

Original languageEnglish
Pages (from-to)943-947
Number of pages5
JournalIn Vivo
Volume23
Issue number6
Publication statusPublished - Nov 1 2009

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Keywords

  • ABCB1
  • ABCC1
  • MDR1
  • MRP1
  • Modulators
  • Multidrug resistance
  • Multidrug resistance-associated protein 1
  • P-glycoprotein
  • Phenothiazine derivatives

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology

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