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Expulsion of Small Molecules in Vesicles Shed by Cancer Cells

Association with Gene Expression and Chemosensitivity Profiles^{1 ,,2}

Department of Statistics, University of Michigan, Ann Arbor, Michigan 48109 [K. S.]; Department of Pharmaceutics, University of Michigan College of Pharmacy, Ann Arbor, Michigan 48109 [X. T. X., P. C., G. R. R.]; and Department of Chemistry, New York University, New York, New York [Y. T. C.]

Anticancer drug resistance results from selective pressure of chemotherapy, together with mutations or epigenetic changes that make cells refractory to treatment. In cancer cells, we report that gene expression associated with vesicle shedding correlates with chemosensitivity profiles. Experiments with doxorubicin and other small molecules confirm drug accumulation and expulsion in shed vesicles. Relative differences in the rate of vesicle shedding correspond with doxorubicin resistance across various cell lines. Moreover, accumulation of drug in membrane domains in which vesicles originate accounts for drug expulsion in shed vesicles. These observations implicate vesicle shedding as a drug efflux mechanism potentially involved in drug resistance.

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