Inhibition of P-glycoprotein transport function by N-acylphenothiazines.

Abstract

Multidrug resistance (mdr) constitutes the major obstacle to successful cancer treatment. The ability of fifteen newly-synthesised N-acylphenothiazine derivatives to inhibit the transport activity of P-glycoprotein was studied by flow cytometry in a resistant mouse lymphoma cell line. A standard functional assay with rhodamine 123 as a fluorescent substrate analogue was used. All derivatives proved to be effective inhibitors of rhodamine 123 outward transport, however their toxicity to the cells was not negligible. Phenothiazine maleates probably interact with transporter proteins of cancer cells by a different mechanism than other phenothiazine derivatives studied. The mdr reversal mechanism of phenothiazine acetylamides, methoxycarbonylamides and methylsulfonylamides is likely to involve modulator-cell membrane interactions since a connection between the compounds' hydrophobicity and their P-glycoprotein inhibition potency was observed. As a result of the present study a new group of mdr reversal agents was identified.

• Authors: Olga Wesolowska, Joseph Molnár, Noboru Motohashi, Krystyna Michalak
• Journal: Anticancer research (Anticancer Res) 2002 Sep-Oct Vol. 22 Issue 5 Pg. 2863-7 ISSN: 0250-7005 [Print] Greece
• PMID: 12530010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Phenothiazines

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Animals
• Drug Resistance, Multiple
• Flow Cytometry
• Genes, MDR
• Leukemia L5178 (drug therapy, genetics, metabolism)
• Mice
• Phenothiazines (pharmacology)
• Structure-Activity Relationship
• Transfection
• Tumor Cells, Cultured