Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells

PLoS One. 2015 Jul 6;10(7):e0131579. doi: 10.1371/journal.pone.0131579. eCollection 2015.


Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Ascites / pathology*
  • Biological Transport / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Multiple / physiology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / physiology
  • Female
  • Genes, MDR / drug effects
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Paclitaxel

Grants and funding

This work was supported by CZ.1.07/2.3.00/30.0009, European Social Fund (VP) (, W81XWH-11-1-0469, Department of Defense Ovarian Cancer Research Program Award (SKM) (, Gail Parkins Ovarian Cancer Research Fund (SKM) (, Internal Reserve Fund of the Department of Pathology, Duke University Medical Center (SVP). The funders had no role in study design,data collection and analysis, decision to publish, or preparation of the manuscript.