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

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 DiOC(2)(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 CF(3)- 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.

• Authors: Andrzej B Hendrich, Olga Wesołowska, Andrzej Poła, Noboru Motohashi, Joseph Molnár, Kystyna Michalak
• Journal: Molecular membrane biology (Mol Membr Biol) 2003 Jan-Mar Vol. 20 Issue 1 Pg. 53-60 ISSN: 0968-7688 [Print] England
• PMID: 12745926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Carbocyanines
• Fluorescent Dyes
• Lipid Bilayers
• Liposomes
• Maleates
• Phenothiazines
• 3,3'-dipentyl-2,2'-oxacarbocyanine
• maleic acid

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Biological Transport (drug effects, physiology)
• Calorimetry
• Carbocyanines (chemistry)
• Cell Membrane (drug effects, metabolism)
• Flow Cytometry (methods)
• Fluorescent Dyes (chemistry)
• Lipid Bilayers (chemistry)
• Liposomes
• Lymphoma (drug therapy)
• Maleates (chemistry)
• Mice
• Phenothiazines (chemistry, pharmacokinetics, pharmacology)
• Spectrometry, Fluorescence
• Structure-Activity Relationship
• Tumor Cells, Cultured