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Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells
Lihong Mo1, Vendula Pospichalova2, Zhiqing Huang3
1Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
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.
Insights
Ovarian cancer ascites promotes chemotherapy resistance by increasing multidrug resistance (MDR) gene expression and drug efflux. Ascites-derived cells show higher susceptibility to MDR inhibitors, revealing a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance is a primary cause of ovarian cancer treatment failure.
- Multidrug resistance (MDR), mediated by ABC transporters, contributes to chemoresistance by exporting drugs from tumor cells.
- Ascites, common in advanced ovarian cancer, is linked to progression, but its role in MDR is unclear.
Purpose of the Study:
- To investigate whether ovarian cancer ascites promotes multidrug resistance (MDR) in ovarian cancer cells.
- To determine the mechanisms by which ascites may influence MDR, focusing on ABC transporters.
- To assess the clinical relevance of ascites-driven MDR in human ovarian cancer.
Main Methods:
- Murine ovarian cancer cells were cultured in ascites and tested for sensitivity to paclitaxel.
- In vitro studies assessed drug efflux function in cells incubated with ascites, using specific inhibitors for MRP1 and BCRP.
- Human ovarian cancer cell lines derived from ascites and primary tumors were compared for efflux activity and ABC transporter expression.
Main Results:
- Murine ovarian cancer cells cultured with ascites exhibited reduced sensitivity to paclitaxel and increased drug efflux.
- Ascites-driven efflux was suppressed by inhibitors of Multidrug Related Protein (MRP1) and Breast Cancer Related Protein (BCRP).
- Human ovarian cancer cells from ascites showed increased efflux, greater susceptibility to MRP1/BCRP inhibitors, and higher ABC transporter expression compared to primary tumor-derived cells.
Conclusions:
- Ovarian cancer ascites actively promotes multidrug resistance (MDR) in ovarian cancer cells.
- Ascites enhances drug efflux, at least partially through MRP1 and BCRP, contributing to chemotherapy resistance.
- These findings highlight ascites as a novel factor driving MDR in ovarian cancer and suggest potential therapeutic strategies targeting ascites-mediated efflux.
