Importance of the Difference in Surface Pressures of the Cell Membrane in Doxorubicin Resistant Cells That do not Expres
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ORIGINAL PAPER
Importance of the Difference in Surface Pressures of the Cell Membrane in Doxorubicin Resistant Cells That do not Express Pgp and ABCG2 Charlotte Bell • Claire Hill • Christopher Burton Adam Blanchard • Freya Shephard • Cyril Rauch
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Published online: 13 January 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract P-glycoprotein (Pgp) represents the archetypal mechanism of drug resistance. But Pgp alone cannot expel drugs. A small but growing body of works has demonstrated that the membrane biophysical properties are central to Pgp-mediated drug resistance. For example, a change in the membrane surface pressure is expected to support drug–Pgp interaction. An interesting aspect from these models is that under specific conditions, the membrane is predicted to take over Pgp concerning the mechanism of drug resistance especially when the surface pressure is high enough, at which point drugs remain physically blocked at the membrane level. However it remains to be determined experimentally whether the membrane itself could, on its own, affect drug entry into cells that have been selected by a low concentration of drug and that do not express transporters. We demonstrate here that in the case of the drug doxorubicin, alteration of the surface pressure of membrane leaflets drive drug resistance. Keywords Drug resistance Pharmacokinetic Membrane Drug transporter P-glycoprotein MDR
C. Bell University of Birmingham, School of Medicine and Dentistry, Edgbaston, Birmingham B15 2TT, UK C. Hill C. Burton A. Blanchard F. Shephard C. Rauch (&) University of Nottingham, School of Veterinary Medicine and Science, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, UK e-mail: [email protected]
Introduction In 2007, the American Cancer Society report concluded that cancer kills *7 m people a year worldwide (1 in 8 deaths). One of the major concerns in this field is that many cancers fail to respond to chemotherapy, by acquiring multi-drug resistance (MDR), to which has been attributed the failure of treatment in over 90 % of patients with metastatic cancer [1]. Furthermore, it is now recognized that cancer aggressiveness, i.e. the metastatic potential of tumours, is related to their resistance to chemotherapy [2, 3]. One major form of resistance to chemotherapy has been correlated with the presence of membrane molecular ‘‘pumps’’ that actively transport drugs out of the cell. Historically, it was in 1973 that Dano Keld suggested that the mechanism of resistance was due to an outward efflux of drugs that ‘‘vacuum clean’’ drugs from cells [4]. This hypothesis gained credence 3 years later when P-glycoprotein (Pgp) was identified as a membrane protein overexpressed in MDR cancer cells that actively extrude membrane-embedded drugs [5]. Since then and further to an important body of works the molecular basis of Pgp is now defined with remarkable precision [6]. Although the molecular model of Pgp has permitted a representation of MD
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