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Elacridar Reverses P-gp-Mediated Drug Resistance in Ovarian Cancer Cells in 2D and 3D Culture Models
Piotr Stasiak1,2,3, Justyna Sopel3, Julia Maria Lipowicz4
1Institute of Biological Sciences, University of Zielona Góra, 65-417 Zielona Góra, Poland.
Abstract:
Multidrug resistance (MDR) remains a major obstacle in the treatment of ovarian cancer. MDR is often mediated by the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. Cells were cultured under both two-dimensional (2D) and three-dimensional (3D) conditions to account for differences in tumor-like microenvironments. The MDR1 gene and P-gp protein expression were determined for the analyzed model; P-gp activity was measured by flow-cytometry and fluorescent observation, with and without elacridar. The MTT tests were carried out to evaluate how elacridar, combined with chemotherapeutics, affects cell viability. Our results demonstrate that elacridar effectively inhibited transporter activity and increased cellular sensitivity to PAC and DOX. The inhibitory effect was observed in both 2D and 3D cultures, although the re-sensitization effect in 3D conditions was less pronounced, reflecting the complexity of tumor-specific resistance mechanisms. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better.
Insights
Elacridar effectively reverses multidrug resistance (MDR) in ovarian cancer by inhibiting P-gp and BCRP transporters. This dual inhibitor enhances chemotherapy sensitivity in both 2D and 3D models, showing promise for overcoming treatment obstacles.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Multidrug resistance (MDR) is a significant challenge in ovarian cancer treatment.
- ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), mediate MDR through overexpression.
- Developing strategies to overcome MDR is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate elacridar, a dual P-gp and BCRP inhibitor, for its efficacy in overcoming MDR in ovarian cancer.
- To assess the impact of elacridar on Paclitaxel (PAC) and Doxorubicin (DOX) sensitivity in ovarian cancer cell lines.
- To investigate the role of 2D and 3D cell culture models in evaluating MDR reversal.
Main Methods:
- Utilized W1 ovarian cancer cell line and its Paclitaxel-resistant variants.
- Cultured cells in both 2D and 3D conditions to mimic tumor microenvironments.
- Measured MDR1 gene and P-gp protein expression, P-gp activity (flow cytometry), and cell viability (MTT assays).
Main Results:
- Elacridar effectively inhibited P-gp and BCRP transporter activity.
- Elacridar increased cellular sensitivity to Paclitaxel (PAC) and Doxorubicin (DOX).
- The re-sensitization effect was observed in both 2D and 3D cultures, though less pronounced in 3D.
Conclusions:
- Elacridar demonstrates significant potential in reversing multidrug resistance in ovarian cancer.
- The study underscores the importance of 3D models for preclinical drug evaluation due to complex resistance mechanisms.
- Further in vitro and in vivo studies are warranted to fully assess elacridar's therapeutic potential.
