The expression of P-glycoprotein does influence the distribution of novel fluorescent compounds in solid tumour models


Solid tumours display a complex drug resistance phenotype that involves inherent and acquired mechanisms. Multicellular resistance is an inherent feature of solid tumours and is known to present significant barriers to drug permeation in tumours. Given this barrier, do acquired resistance mechanisms such as P-glycoprotein (P-gp) contribute significantly to resistance? To address this question, the multicellular tumour spheroid (MCTS) model was used to examine the influence of P-gp on drug distribution in solid tissue. Tumour spheroids (TS) were generated from either drug-sensitive MCF7WT cells or a drug-resistant, P-gp-expressing derivative MCF7Adr. Confocal microscopy was used to measure time courses and distribution patterns of three fluorescent compounds; calcein-AM, rhodamine123 and BODIPY-taxol. These compounds were chosen because they are all substrates for P-gp-mediated transport, exhibit high fluorescence and are chemically dissimilar. For example, BODIPY-taxol and rhodamine 123 showed high accumulation and distributed extensively throughout the TSWT, whereas calcein-AM accumulation was restricted to the outermost layers. The presence of P-gp in TSAdr resulted in negligible accumulation, regardless of the compound. Moreover, the inhibition of P-gp by nicardipine restored intracellular accumulation and distribution patterns to levels observed in TSWT. The results demonstrate the effectiveness of P-gp in modulating drug distribution in solid tumour models. However, the penetration of agents throughout the tissue is strongly determined by the physico-chemical properties of the individual compounds.

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Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: Creative Commons Non-commercial Share-alike
Uncontrolled Keywords: antineoplastic agents,multiple drug resistance,fluoresceins,fluorescent dyes,humans,confocal microscopy,P-glycoprotein,paclitaxel,rhodamine 123,cellular spheroids,tumor models
Publication ISSN: 1532-1827
Last Modified: 16 May 2024 07:08
Date Deposited: 11 Mar 2019 18:18
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Related URLs: http://www.natu ... l/6601300a.html (Publisher URL)
PURE Output Type: Article
Published Date: 2003-10
Authors: Martin, C.
Walker, J.
Rothnie, A. (ORCID Profile 0000-0002-4259-7015)
Callaghan, R.

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