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Patterns of cell death induced by metformin in human MCF-7 breast cancer cells
Natália Medeiros Dias Lopes1, Poliana Camila Marinello1, Larissa Juliani Sanches1
1Laboratory of Molecular Pathology, State University of Londrina, Londrina, PR, Brazil.
Abstract:
The ability to evade apoptosis is an important mechanism of drug resistance and tumor progression in breast cancer. The induction of different pathways of cell death could be an important strategy to limit tumor progression. Metformin, a drug used to treat type two diabetes, has demonstrated promising results in breast cancer experiments. However, little is known about the patterns of cell death induced by this drug. We analyzed the involvement of apoptosis, necroptosis and ferroptosis in the toxicity of metformin in MCF-7 cells, evaluating proliferation, viability and oxidative stress. It was used different inhibitors of cell death: Z-VAD, a pan-caspase inhibitor that blocks apoptosis; Necrostatin-1, which inhibits RIPK1 activity and blocks necroptosis; and the iron chelator, deferoxamine, that chelates iron and prevents ferroptosis. The participation of oxidative stress was analyzed through the evaluation of total thiols, reduced glutathione (GSH) and malondialdehyde (MDA). Our results showed that metformin increased cell death, reduced proliferation, thiol and GSH and increased MDA in cells. After the association between metformin and Z-VAD or Necrostatin-1, the drug toxicity was abolished. Ferroptosis did not significantly enrolled in metformin action against MCF-7 cells. The preservation of cellular antioxidants was found in all situations that cell death was blocked. Together, these results reveals that metformin induces necroptosis and apoptosis in MCF-7 cells and oxidative stress generation play a role in these two pathways of cell death. This information could help future studies to improve strategies to breast cancer treatment.
Insights
Metformin induces both apoptosis and necroptosis, contributing to cell death in breast cancer cells. This mechanism involves oxidative stress, offering new therapeutic strategies for breast cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Evasion of apoptosis is a key mechanism in breast cancer drug resistance and progression.
- Targeting diverse cell death pathways is a potential strategy to combat tumor growth.
- Metformin, a diabetes drug, shows promise in preclinical breast cancer models, but its cell death mechanisms are unclear.
Purpose of the Study:
- To investigate the roles of apoptosis, necroptosis, and ferroptosis in metformin-induced toxicity in MCF-7 breast cancer cells.
- To evaluate the impact of metformin on cell proliferation, viability, and oxidative stress.
- To elucidate the specific cell death pathways activated by metformin.
Main Methods:
- MCF-7 cells were treated with metformin and specific cell death inhibitors (Z-VAD for apoptosis, Necrostatin-1 for necroptosis, deferoxamine for ferroptosis).
- Proliferation, viability, and oxidative stress markers (total thiols, GSH, MDA) were assessed.
- The effects of metformin combined with inhibitors on cell death were analyzed.
Main Results:
- Metformin increased cell death, reduced proliferation, and altered oxidative stress markers (decreased thiols and GSH, increased MDA).
- Inhibiting apoptosis (Z-VAD) or necroptosis (Necrostatin-1) abolished metformin's toxicity.
- Ferroptosis did not appear to be significantly involved in metformin's anti-cancer effects.
- Cellular antioxidant levels were preserved when cell death pathways were blocked.
Conclusions:
- Metformin induces cell death in MCF-7 cells primarily through apoptosis and necroptosis.
- Oxidative stress plays a significant role in mediating metformin-induced apoptosis and necroptosis.
- Understanding these mechanisms can inform the development of improved breast cancer therapies.
