title: Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells.
abstract: 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.
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
authors.forename: Vandhana
authors.initials: V
authors.lastname: Muralidharan-Chari
authors.affiliation: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.
authors.forename: Hamed Gilzad
authors.initials: HG
authors.lastname: Kohan
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, NY 12201, USA.
authors.forename: Alexandros G
authors.initials: AG
authors.lastname: Asimakopoulos
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
authors.forename: Thangirala
authors.initials: T
authors.lastname: Sudha
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, NY 12201, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Sell
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, NY 12201, USA.
authors.forename: Kurunthachalam
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Boroujerdi
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.|Department of Medicine, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D059016:Tumor Microenvironment; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: drug expulsion; drug resistance; microvesicles; pancreatic cancer; transporter proteins