Patterns of cell death induced by metformin in human MCF-7 breast cancer cells

Lopes, Natália Medeiros Dias; Marinello, Poliana Camila; Sanches, Larissa Juliani; Brito, Walison Augusto da Silva; Lovo‐Martins, Maria Isabel; Pinge‐Filho, Phileno; Luiz, Rodrigo Cabral; Cecchini, Rúbens; Cecchini, Alessandra Lourenço

doi:10.1016/j.prp.2020.153199

Cited by 14 publications

(12 citation statements)

References 51 publications

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“…This means that compounds 11 and 20 could induce apoptosis in cancer cells by triggering intracellular ROS and inhibiting endogenous antioxidant enzymes. Increased production of ROS in cancer cells leads to the activation of AMPK protein kinase and also causes mitochondrial membrane dysfunction, which finally induces apoptosis and arrests cell survival and proliferation [ 47 , 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…The second pathway involves the ability of compounds 11 and 20 to act on ROS generation, leading to mitochondrial membrane dysfunction and in turn causing an increase in Bax and a decrease in Bcl- 2 , thereby increasing cytochrome C and caspase 3. These mechanical pathways induce apoptosis and arrest cell survival and proliferation [ 3 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

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New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway

et al. 2021

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Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3–11 and indole 12–20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of −8.8, −13.0, −7.9, and −10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 μg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 μg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski’s rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway

et al. 2021

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“…On the other hand, it can promote ROS generation, leading to autophosphorylation at S161 of RIPK1 to trigger necroptosis. However, the cytotoxic effects of metformin could be alleviated through the administration of necrostatin-1 (Nec-1), a RIPK1 inhibitor [67]. Simvastatin is a statin drug and functions as an HMG-CoA reductase inhibitor widely prescribed for patients with hypercholesterolemia [68].…”

Section: Necroptosismentioning

confidence: 99%

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

Hsu

Cheng

Mgbeahuruike

et al. 2021

IJMS

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Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.

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“…With regards to mortality, it occupies the second position. Due to these facts, the scientists concentrated their efforts on the evaluation of metformin therapeutic potential in this type of cancer [ 13 , 14 , 15 ]. For instance, Jiralerspong et al [ 16 ] reported that diabetic patients receiving neoadjuvant chemotherapy demonstrated a greater response rate (24% in the metformin group vs. 8% in the non-metformin group) compared with patients who were administered other anti-diabetic drugs.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of MDA-MB-231 cells, death and decreased proliferation were reported only at higher doses. 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.…”

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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Patterns of cell death induced by metformin in human MCF-7 breast cancer cells

Cited by 14 publications

References 51 publications

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

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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