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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

Wesolowska O,Molnár J,Motohashi N,Michalak K

subject

Has Abstract

pub_date

2002-09-01 00:00:00

pages

2863-7

issue

5

eissn

0250-7005

issn

1791-7530

journal_volume

22

pub_type

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