Open AccessMicrovesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells
Author(s) -
Vandhana MuralidharanChari,
Hamed Gilzad Kohan,
Alexandros G. Asimakopoulos,
Thangirala Sudha,
Stewart Sell,
Kurunthachalam Kannan,
Mehdi Boroujerdi,
Paul J. Davis,
Shaker A. Mousa
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.10395
Subject(s) - pancreatic cancer , pharmacy , medicine , pharmaceutical sciences , gemcitabine , drug resistance , cancer , biomedical sciences , pharmacology , family medicine , pathology , biology , microbiology and biotechnology
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.