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Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer
1Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA.
Objectives:
BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells.
Methods:
Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry.
Results:
Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo.
Conclusion:
Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status.
Insights
Combining metformin with olaparib, a PARP inhibitor, shows significant anti-proliferative effects in ovarian cancer cells. This combination therapy is effective in both BRCA-mutated and BRCA-intact ovarian cancers, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- BRCA-mutated ovarian cancers exhibit heightened sensitivity to PARP inhibitors due to synthetic lethality.
- PARP inhibitors exploit DNA repair deficiencies in cancer cells.
- Investigating novel therapeutic combinations to overcome resistance and broaden treatment applicability is crucial.
Purpose of the Study:
- To evaluate the synergistic anti-cancer effects of combining metformin with olaparib (a PARP inhibitor) in BRCA-intact ovarian cancer cells.
- To determine the efficacy of this combination in vitro and in vivo models.
- To explore the underlying molecular mechanisms of the combination therapy.
Main Methods:
- Ovarian cancer cell lines were treated with metformin and olaparib.
- Cell viability was assessed using MTT and colony formation assays.
- Cell cycle progression and tumor xenografts in mice were analyzed to evaluate treatment effects.
Main Results:
- The combination of metformin and olaparib significantly reduced ovarian cancer cell proliferation and colony formation compared to single agents.
- The treatment induced S-phase cell cycle arrest and inhibited tumor growth in vivo.
- Metformin potentiated olaparib-induced AMPK activation in vivo without affecting DNA damage signaling.
Conclusions:
- Combining PARP inhibitors with metformin enhances anti-proliferative activity in ovarian cancer cells.
- This combination demonstrates significant efficacy in both BRCA-mutated and BRCA-intact ovarian cancer models.
- The metformin-olaparib regimen presents a promising therapeutic option for epithelial ovarian cancer, regardless of BRCA mutation status.
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