Neither lipophilicity nor membrane-perturbing potency of phenothiazine maleates correlate with the ability to inhibit P-glycoprotein transport activity

Andrzej B. Hendrich, Olga Wesołowska, Andrzej Poła, Noboru Motohashi, J. Molnár, Krystyna Michalak

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Although phenothiazines are known as multidrug resistance modifiers, the molecular mechanism of their activity remains unclear. Since phenothiazine molecules are amphiphilic, the interactions with membrane lipids may be related, at least partially, to their biological effects. Using the set of phenothiazine maleates differing in the type of phenothiazine ring substitution at position 2 and/or in the length of the alkyl bridge-connecting ring system and side chain group, we investigated if their ability to modulate the multidrug resistance of cancer cells correlated with model membrane perturbing potency. The influence exerted on lipid bilayers was determined by liposome/buffer partition coefficient measurements (using the absorption spectra second-derivative method), fluorescence spectroscopy and calorimetry. Biological effects were assessed by a flow cytometric functional test based on differential accumulation of fluorescent probe DiOC2(3) by parental and drug-resistant cells. We found that all phenothiazine maleates were incorporated into lipid bilayers and altered their biophysical properties. With only few exceptions, the extent of membrane perturbation induced by phenothiazine maleates correlated with their lipophilicity. Within the group of studied derivatives, the compounds substituted with CF3- at position 2 of phenothiazine ring were the most active membrane perturbants. No clear relation was found between effects exerted by phenothiazine maleates on model membranes and their ability to modulate P-glycoprotein transport activity.

Original languageEnglish
Pages (from-to)53-60
Number of pages8
JournalMolecular Membrane Biology
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2003

Fingerprint

Maleates
P-Glycoprotein
Membranes
Lipid Bilayers
Multiple Drug Resistance
Phenothiazines
Calorimetry
Fluorescence Spectrometry
Membrane Lipids
phenothiazine
Fluorescent Dyes
Liposomes
Buffers

Keywords

  • Drug-lipid interactions
  • Lipid bilayer fluidity
  • Multidrug resistance reversal
  • P-glycoprotein
  • Phenothiazine derivatives

ASJC Scopus subject areas

  • Cell Biology

Cite this

Neither lipophilicity nor membrane-perturbing potency of phenothiazine maleates correlate with the ability to inhibit P-glycoprotein transport activity. / Hendrich, Andrzej B.; Wesołowska, Olga; Poła, Andrzej; Motohashi, Noboru; Molnár, J.; Michalak, Krystyna.

In: Molecular Membrane Biology, Vol. 20, No. 1, 01.2003, p. 53-60.

Research output: Contribution to journalArticle

Hendrich, Andrzej B. ; Wesołowska, Olga ; Poła, Andrzej ; Motohashi, Noboru ; Molnár, J. ; Michalak, Krystyna. / Neither lipophilicity nor membrane-perturbing potency of phenothiazine maleates correlate with the ability to inhibit P-glycoprotein transport activity. In: Molecular Membrane Biology. 2003 ; Vol. 20, No. 1. pp. 53-60.
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