Regular Article

British Journal of Cancer (2001) 85, 1998–2003. doi:10.1054/bjoc.2001.2184 www.bjcancer.com
Published online 11 December 2001

Selective modulation of P-glycoprotein-mediated drug resistance

M Bebawy1, M B Morris1 and B D Roufogalis1

1Faculty of Pharmacy, The University of Sydney, N.S.W, 2006, Australia

Received 23 January 2001; Revised 3 August 2001; Accepted 21 September 2001.

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Abstract

Multidrug resistance associated with the overexpression of the multidrug transporter P-glycoprotein is a serious impediment to successful cancer treatment. We found that verapamil reversed resistance of CEM/VLB100 cells to vinblastine and fluorescein-colchicine, but not to colchicine. Chlorpromazine reversed resistance to vinblastine but not to fluorescein-colchicine, and it increased resistance to colchicine. Initial influx rates of fluorescein-colchicine were similar in resistant and parental cells, whereas vinblastine uptake was about 10-fold lower in the resistant cells. These results provide indirect evidence that fluorescein-colchicine is transported from the inner leaflet of the membrane and vinblastine from the outer membrane leaflet. Verapamil inhibited fluorescein-colchicine transport in inside-out vesicles made from resistant cells, whilst chlorpromazine was found to activate the transport of fluorescein-colchicine. The chlorpromazine-induced activation of fluorescein-colchicine transport was temperature-dependent and may reflect its interaction with phospholipids localised in the same bilayer leaflet. Conversely, chlorpromazine localisation in this leaflet may be responsible for its allosteric inhibition of vinblastine transport from the opposing membrane leaflet. The proposed relationship between the selectivity of modulation of P-glycoprotein and the membrane localisation of the cytotoxic drug substrates and modulators may have important implications in the rational design of regimes for the circumvention of multidrug resistance clinically. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

chlorpromazine, colchicine, fluorescein-colchicine, multidrug resistance, P-glycoprotein, vinblastine

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