Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells
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Vandhana Muralidharan-Chari1, Hamed Gilzad Kohan2,*, Alexandros G. Asimakopoulos3, Thangirala Sudha1, Stewart Sell3, Kurunthachalam Kannan3, Mehdi Boroujerdi2,**, Paul J. Davis1,4, Shaker A. Mousa1
1The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA
2Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
3Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, NY 12201, USA
4Department of Medicine, Albany Medical College, Albany, NY 12208, USA
*Present address: College of Pharmacy, Western New England University, Springfield, MA, USA
**Present address: Department of Pharmaceutical and Administrative Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Massachusetts, Lowell, MA, USA
Vandhana Muralidharan-Chari, email: [email protected]
Keywords: drug expulsion, drug resistance, microvesicles, pancreatic cancer, transporter proteins
Received: March 11, 2016 Accepted: June 17, 2016 Published: July 04, 2016
High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line’s sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.
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