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Carboplatin sensitivity in epithelial ovarian cancer cell lines: The impact of model systems
Bishnubrata Patra1,2, Muhammad Abdul Lateef2, Melica Nourmoussavi Brodeur2
1Department of Engineering Physics and Institute of Biomedical Engineering, École Polytechnique de Montréal, Montréal, QC, Canada.
Abstract:
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America, underscoring the need for the development of new therapeutic strategies for the management of this disease. Although many drugs are pre-clinically tested every year, only a few are selected to be evaluated in clinical trials, and only a small number of these are successfully incorporated into standard care. Inaccuracies with the initial in vitro drug testing may be responsible for some of these failures. Drug testing is often performed using 2D monolayer cultures or 3D spheroid models. Here, we investigate the impact that these different in vitro models have on the carboplatin response of four EOC cell lines, and in particular how different 3D models (polydimethylsiloxane-based microfluidic chips and ultra low attachment plates) influence drug sensitivity within the same cell line. Our results show that carboplatin responses were observed in both the 3D spheroid models tested using apoptosis/cell death markers by flow cytometry. Contrary to previously reported observations, these were not associated with a significant decrease in spheroid size. For the majority of the EOC cell lines (3 out of 4) a similar carboplatin response was observed when comparing both spheroid methods. Interestingly, two cell lines classified as resistant to carboplatin in 2D cultures became sensitive in the 3D models, and one sensitive cell line in 2D culture showed resistance in 3D spheroids. Our results highlight the challenges of choosing the appropriate pre-clinical models for drug testing.
Insights
Pre-clinical drug testing for epithelial ovarian cancer (EOC) using 3D spheroid models reveals altered carboplatin sensitivity compared to 2D cultures. These findings highlight challenges in selecting appropriate in vitro models for drug development.
Area of Science:
- Oncology
- Biotechnology
- Drug Discovery
Background:
- Epithelial ovarian cancer (EOC) is a leading cause of cancer death in North America, necessitating novel therapeutic strategies.
- Current pre-clinical drug testing faces limitations, potentially leading to failures in clinical translation.
- In vitro drug screening commonly employs 2D monolayer and 3D spheroid models, with varying impacts on drug response.
Purpose of the Study:
- To investigate the influence of different in vitro models on carboplatin response in EOC cell lines.
- To compare carboplatin sensitivity across 2D cultures, microfluidic chips, and ultra-low attachment plates for 3D spheroid models.
- To assess how model choice affects the classification of EOC cell line sensitivity to carboplatin.
Main Methods:
- Utilized four epithelial ovarian cancer (EOC) cell lines for in vitro drug testing.
- Compared carboplatin response in 2D monolayer cultures versus two distinct 3D spheroid models (microfluidic chips and ultra-low attachment plates).
- Assessed drug response using apoptosis/cell death markers via flow cytometry.
Main Results:
- Carboplatin induced apoptosis/cell death in 3D spheroid models, independent of significant spheroid size reduction.
- Similar carboplatin responses were observed between the two tested 3D spheroid models for most EOC cell lines (3/4).
- Significant discrepancies in carboplatin sensitivity were noted between 2D and 3D models, with some resistant cell lines becoming sensitive and vice versa.
Conclusions:
- The choice of in vitro model significantly impacts the assessment of carboplatin efficacy in epithelial ovarian cancer.
- 3D spheroid models offer a more predictive platform for carboplatin response compared to traditional 2D cultures.
- These findings underscore the critical need for careful selection of pre-clinical models to improve drug development success rates for EOC.
