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Sensitivity and Resistance to Therapy

Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells

Abstract

Multidrug resistance (MDR), a significant impediment to the successful treatment of cancer clinically, has been attributed to the overexpression of P-glycoprotein (P-gp), a plasma membrane multidrug efflux transporter. P-gp maintains sublethal intracellular drug concentrations by virtue of its drug efflux capacity. The cellular regulation of P-gp expression is currently known to occur at either pre- or post-transcriptional levels. In this study, we identify a ‘non-genetic’ mechanism whereby microparticles (MPs) serve as vectors in the acquisition and spread of MDR. MPs isolated from drug-resistant cancer cells (VLB100) were co-cultured with drug sensitive cells (CCRF–CEM) over a 4 h period to allow for MP binding and P-gp transfer. Presence of P-gp on MPs was established using flow cytometry (FCM) and western blotting. Whole-cell drug accumulation assays using rhodamine 123 and daunorubicin (DNR) were carried out to validate the transfer of functional P-gp after co-culture. We establish that MPs shed in vitro from drug-resistant cancer cells incorporate cell surface P-gp from their donor cells, effectively bind to drug-sensitive recipient cells and transfer functional P-gp to the latter. These findings serve to substantially advance our understanding of the molecular basis for the emergence of MDR in cancer clinically and lead to new treatment strategies which target and inhibit MP mediated transfer of P-gp during the course of treatment.

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Abbreviations

DNR:

Daunorubicin

FCM:

Flow cytometry

MDR:

Multiple Drug Resistance

MP:

Microparticles

P-gp:

P-glycoprotein

R123:

Rhodamine 123

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Acknowledgements

This work was supported by The University of Sydney funds to Dr M Bebawy and to Professor G Grau.

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Correspondence to M Bebawy or G E R Grau.

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Bebawy, M., Combes, V., Lee, E. et al. Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells. Leukemia 23, 1643–1649 (2009). https://doi.org/10.1038/leu.2009.76

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