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

Vitezslav Bryja,Margaret Kennedy,Salvatore V Pizzo,Sturgis Payne,Fang Wang,Susan K Murphy,Lihong Mo,Robin E Bachelder,Zhiqing Huang,George J Cianciolo,Vendula Pospichalova

doi:10.1371/journal.pone.0131579

Vitezslav Bryja, Margaret Kennedy + Show 9 more

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https://doi.org/10.1371/journal.pone.0131579

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Journal: PloS one	Publication Date: Jul 6, 2015
Citations: 36	License type: CC BY 4.0

Affiliation: Duke University Hospital, Duke Medical Center

Abstract

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.

Highlights

Operative tumor debulking is performed mainly on stage I/II ovarian cancer patients
We studied the expression of three ATP-binding cassette (ABC) transporter genes (MDR1, MRP1 and Breast Cancer Related Protein (BCRP)) that are commonly involved in cancer chemo-resistance
We demonstrate that murine ovarian cancer cells (ID8) exhibit increased taxane chemo-resistance when exposed to ascites in vitro or in vivo

Summary

Introduction

Operative tumor debulking is performed mainly on stage I/II ovarian cancer patients. This surgical procedure for advanced stage disease (III to IV) is not always possible, especially in women whose disease is extensive [1]. Chemotherapy is the primary tool for blocking dissemination of cancer cells when clinicians treat patients at advanced cancer stages. The first-line chemotherapy for ovarian cancer has remained unchanged over the last decade, with the therapeutic backbone consisting of a platinum agent (generally carboplatin) and a taxane (generally paclitaxel) [3]. Second-line chemotherapies are considered when the patients are unresponsive to first-line drugs. A number of antineoplastic agents have demonstrated sufficient biological activity to be considered rational second-line choices, such as doxorubicin, etoposide, gemcitabine, ifosfamide, or cyclophosphamide [4]

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