Oxidative stress and TGF-β1 induction by metformin in MCF-7 and MDA-MB-231 human breast cancer cells are accompanied with the downregulation of genes related to cell proliferation, invasion and metastasis

Marinello, Poliana Camila; Silva, Thamara N.X.; Binato, Renata; Abdelhay, Eliana; Rodrigues, Juliana Alves; Mencalha, André Luiz; Lopes, Natália Medeiros Dias; Borges, Fernando H.; Luiz, Rodrigo Cabral; Cecchini, Rúbens; Cecchini, Alessandra Lourenço

doi:10.1016/j.prp.2020.153135

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…However, metformin has been reported to inhibit the AGE formation [ 67 ]. In addition, a number of studies have reported that metformin could downregulate RAGE expression and reduce NF- κ B activation in various cells, including osteoblastic cells [ 68 – 70 ], MCF-7, MDA-MB-231 cells [ 71 ], and osteosarcoma stem cells [ 72 ]. Moreover, Bian et al reported [ 73 ] that low concentration of metformin inhibited osteoclast differentiation, as well as downregulated catK expression, and its inhibitory effect was gradually enhanced with increasing concentrations of metformin.…”

Section: Discussionmentioning

confidence: 99%

Lycopene Improves Bone Quality and Regulates AGE/RAGE/NF-кB Signaling Pathway in High-Fat Diet-Induced Obese Mice

Xia

Zhu

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. This study was aimed at examining the effects of lycopene on bone metabolism in high-fat diet (HFD)- induced obese mice and to identify the potential underlying mechanisms. Methods. Mice were fed a HFD for 12 weeks and then continue with or without lycopene intervention (15 mg/kg) for additional 10 weeks. The effects of lycopene on blood glucose and lipid metabolism, as well as serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and malondialdehyde (MDA) were determined by biochemical assays. Bone histomorphological features and osteoclast activity were assessed by hematoxylin/eosin and tartrate-resistant acid phosphatase staining. Bone microstructure at the proximal tibial metaphysis and diaphysis was determined by microcomputed tomography. Tibial biomechanical strength and material profiles were measured by a three-point bending assay and Fourier transform infrared spectroscopy. Protein expressions involved in the AGE/RAGE/NF-кB signaling pathway were determined by western blot and/or immunohistochemical staining. Results. Lycopene consumption reduced body weight gain and improved blood glucose and lipid metabolism in HFD-induced obese mice. In addition, lycopene treatment preserved bone biomechanical strength, material profiles, and microarchitecture in obese mice. Moreover, these alterations were associated with an increase in serum levels of T-AOC and SOD, and a decline in serum levels of MDA, as well as a reduction of AGEs, RAGE, cathepsin K, and p-NF-кBp65 and NF-кBp65 expressions in the femurs and tibias of obese mice. Conclusion. Lycopene may improve bone quality through its antioxidant properties, which may be linked with the regulation of the AGE/RAGE/NF-кB signaling pathway in obese mice. These results suggest that lycopene consumption may be beneficial for the management of obesity-induced osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Lycopene Improves Bone Quality and Regulates AGE/RAGE/NF-кB Signaling Pathway in High-Fat Diet-Induced Obese Mice

Xia

Zhu

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Marinello et al (2020) found that MET treatment-induced lipoperoxidation and reduced total thiol and NO/peroxynitrite levels in cells. MET treatment also interfered with signaling pathways related to OS and cell survival, as treatment increased nuclear p53, consistent with our enrichment results [54]. Of note, reduction in viability mediated by apoptosis has also been demonstrated in our results and studies on the subject [53,55,56].…”

Section: Discussionmentioning

confidence: 91%

“…They also concluded that the growth inhibitory effect of MET on BC-derived cells is associated with a reduction in ROS production [53]. Marinello et al (2020) found that MET treatment-induced lipoperoxidation and reduced total thiol and NO/peroxynitrite levels in cells. MET treatment also interfered with signaling pathways related to OS and cell survival, as treatment increased nuclear p53, consistent with our enrichment results [54].…”

Section: Discussionmentioning

confidence: 99%

Microarray Analysis of Breast Cancer Gene Expression Profiling in Response to 2-Deoxyglucose, Metformin, and Glucose Starvation

Aoun¹,

Hadi²,

Tahtouh³

et al. 2021

Preprint

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Background: Breast cancer (BC) is the most frequently diagnosed cancer in women. Altering glucose metabolism and its effects on cancer progression and treatment resistance is an emerging interest in BC research. For instance, combining chemotherapy with glucose-lowering drugs (2-deoxyglucose (2-DG), metformin) or glucose starvation (GS) has shown better outcomes than with chemotherapy alone. However, the genes and molecular mechanisms that govern the action of these glucose deprivation conditions have not been fully elucidated. Here, we compared the effect of glucose deprivation (2-DG, metformin, GS) on MDA-MB-231 and MCF-7 BC cell lines using microarray analysis to establish a database of differentially expressed genes and enrichment pathways, in order to investigate the beneficial effect of glucose-lowering treatments on the vulnerability of BC cells.Methods: MDA-MB-231 and MCF-7 cells were treated with 20 mM metformin or 4 mM 2-DG for 48 hours. GS was performed by gradually decreasing the concentration of glucose in the culture medium to 0 g/L with fetal bovine serum over 1 week. Expression profiling was carried out using Affymetrix Human Clariom S microarrays. Differentially expressed genes were obtained from the Transcriptome Analysis Console and enriched using DAVID and R packages.Results: Our results showed that MDA-MB-231 cells were more responsive to glucose deprivation than MCF-7 cells. Endoplasmic reticulum stress response and cell cycle inhibition were detected after all three glucose deprivations in MDA-MB-231 cells and only under the metformin and GS conditions in MCF-7 cells. Induction of apoptosis and inhibition of DNA replication were observed with all three treatments in MDA-MB-231 cells and metformin-treated MCF-7 cells. Upregulation of cellular response to reactive oxygen species and inhibition of DNA repair mechanisms resulted after metformin and GS administration in MDA-MB-231 cell lines and metformin-treated MCF-7 cells. Autophagy was induced after 2-DG treatment in MDA-MB-231 cells and after metformin in MCF-7 cells. Finally, enhanced cell-cell adhesion and inhibition of DNA methylation and cholesterol biosynthesis were observed with GS only in MDA-MB-231 cells. Conclusion: GS had the greatest effect on breast cancer cells compared to 2-DG and metformin. Our results suggest that the combination of metformin and GS should weaken both cell lines and makes them more vulnerable to conventional chemotherapy.

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“…The biological activity of metformin in MCF-7 and MDA-MB-231 cells has been particularly well examined. These two cell lines are frequently chosen because they correspond to different subtypes of breast cancer: luminal (positive for estrogen and progesterone receptors and negative for HER-2 receptor) and triple negative (TNBC), respectively [ 18 ]. Marinello et al (2020) reported that clinical concentrations of metformin decrease the metabolic activity of MCF-7 cells; however, cell death and decreased cellular proliferation were observed at higher experimental concentrations (1–5 mM).…”

Section: Introductionmentioning

confidence: 99%

“…It was also found that metformin reduces cell survival by increasing the production of reactive oxygen species (ROS), which induce DNA damage, apoptosis [ 15 ] and necroptosis [ 13 ]. Further studies of Marinello’s team [ 18 ] confirmed that metformin upregulates genes involved in oxidative stress generation and apoptosis, and downregulates genes associated with metastasis in MCF-7 cells. In MDA-MB-231 cells, metformin downregulated genes involved in cell invasion, viability and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells

Markowicz-Piasecka

Sadowski

Huttunen

et al. 2021

IJMS

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Metformin, apart from its glucose-lowering properties, has also been found to demonstrate anti-cancer properties. Anti-cancer efficacy of metformin depends on its uptake in cancer cells, which is mediated by plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs). This study presents an analysis of transporter mediated cellular uptake of ten sulfonamide-based derivatives of metformin in two breast cancer cell lines (MCF-7 and MDA-MB-231). Effects of these compounds on cancer cell growth inhibition were also determined. All examined sulfonamide-based analogues of metformin were characterized by greater cellular uptake in both MCF-7 and MDA-MB-231 cells, and stronger cytotoxic properties than those of metformin. Effective intracellular transport of the examined compounds in MCF-7 cells was accompanied by high cytotoxic activity. For instance, compound 2 with meta-methyl group in the benzene ring inhibited MCF-7 growth at micromolar range (IC50 = 87.7 ± 1.18 µmol/L). Further studies showed that cytotoxicity of sulfonamide-based derivatives of metformin partially results from their ability to induce apoptosis in MCF-7 and MDA-MB-231 cells and arrest cell cycle in the G0/G1 phase. In addition, these compounds were found to inhibit cellular migration in wound healing assay. Importantly, the tested biguanides are more effective in MCF-7 cells at relatively lower concentrations than in MDA-MB-231 cells, which proves that the effectiveness of transporter-mediated accumulation in MCF-7 cells is related to biological effects, including MCF-7 cell growth inhibition, apoptosis induction and cell cycle arrest. In summary, this study supports the hypothesis that effective transporter-mediated cellular uptake of a chemical molecule determines its cytotoxic properties. These results warrant a further investigation of biguanides as putative anti-cancer agents.

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Oxidative stress and TGF-β1 induction by metformin in MCF-7 and MDA-MB-231 human breast cancer cells are accompanied with the downregulation of genes related to cell proliferation, invasion and metastasis

Cited by 10 publications

References 40 publications

Lycopene Improves Bone Quality and Regulates AGE/RAGE/NF-кB Signaling Pathway in High-Fat Diet-Induced Obese Mice

Lycopene Improves Bone Quality and Regulates AGE/RAGE/NF-кB Signaling Pathway in High-Fat Diet-Induced Obese Mice

Microarray Analysis of Breast Cancer Gene Expression Profiling in Response to 2-Deoxyglucose, Metformin, and Glucose Starvation

Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells

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