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Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells
Sara Mikhael1, Abdullah Kurdi2, Nathalie Khoueiry-Zgheib3
1Laboratory of Cancer and Metabolism, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon.
Background:
Ovarian Cancer (OC) stands as the most lethal gynecological malignancy, presenting an urgent clinical challenge in the quest to improve response rates. One approach to address this challenge is through drug repurposing, exemplified by the investigation of metabolic-modulating drugs such as Metformin (MTF) and Simvastatin (SIM). This study aims to explore the molecular mechanisms contributing to the potential synergistic anti-cancer effects between MTF and SIM on ovarian cancer cells.
Methods:
We assessed the effects of the combination on the proliferation and viability of two cell lines OVCAR-3 and SKOV-3. IC50 concentrations of MTF and SIM were determined using a proliferation assay, followed by subtoxic concentrations to explore the potential synergistic effects on the viability of both cell lines. Transcriptomic analysis was conducted on OVCAR-3 treated cells, and the findings were validated by assessing the expression levels of differentially expressed genes (DEGs) through real-time PCR in both cell lines SK-OV-3 and OVCAR-3.
Results:
Cytotoxicity analysis guided the selection of treatment concentrations as such MTF 10 mM and SIM 5 μM. The combined treatment of MTF and SIM demonstrated a synergistic inhibition of proliferation and viability in both cell lines. In OVCAR-3, exclusive identification of 507 DEGs was seen in the combination arm. Upregulation of FOXO3, RhoA, and TNFα, along with downregulation of PIK3R1, SKP2, and ATP6V1D levels, was observed in OVCAR-3 treated cells. Real-time PCR validation confirmed the consistency of expression levels for the mentioned DEGs.
Conclusion:
Our data strongly supports the presence of synergy between MTF and SIM in OC cells. The combination's effect is associated with the dysregulation of genes in the key regulators AMPK and mTOR alongside other interconnected pathways.
Insights
Metformin (MTF) and Simvastatin (SIM) show synergistic effects against ovarian cancer (OC) by inhibiting cell proliferation and viability. This combination impacts key molecular pathways, offering a potential new therapeutic strategy for OC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Ovarian cancer (OC) is a leading cause of gynecological cancer mortality.
- Drug repurposing of metabolic-modulating agents like Metformin (MTF) and Simvastatin (SIM) is explored to improve treatment efficacy.
- Understanding the synergistic molecular mechanisms of MTF and SIM in OC is crucial.
Purpose of the Study:
- To investigate the synergistic anti-cancer effects of Metformin (MTF) and Simvastatin (SIM) combination on ovarian cancer (OC) cells.
- To elucidate the molecular mechanisms underlying the synergistic effects of MTF and SIM.
- To assess the impact of the drug combination on cell proliferation, viability, and gene expression.
Main Methods:
- Ovarian cancer cell lines (OVCAR-3, SKOV-3) were treated with varying concentrations of MTF and SIM.
- IC50 values were determined, and subtoxic concentrations were used to assess synergistic effects on proliferation and viability.
- Transcriptomic analysis and real-time PCR were employed to identify and validate differentially expressed genes (DEGs).
Main Results:
- The combination of MTF (10 mM) and SIM (5 μM) exhibited synergistic inhibition of proliferation and viability in both OC cell lines.
- Transcriptomic analysis in OVCAR-3 cells revealed 507 differentially expressed genes (DEGs) unique to the combination treatment.
- Key gene expression changes included upregulation of FOXO3, RhoA, TNFα, and downregulation of PIK3R1, SKP2, ATP6V1D, validated by real-time PCR.
Conclusions:
- The study provides strong evidence for synergy between Metformin and Simvastatin in ovarian cancer cells.
- The observed synergistic effects are linked to the dysregulation of genes involved in critical pathways, including AMPK and mTOR.
- This combination therapy holds potential as a novel strategy for ovarian cancer treatment.
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