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Cancer Biology & Therapy Dec 2023The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human...
The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human colon cancer cells. Metformin increased cellular FOXO3a, p-FOXO3a, AMPK, p-AMPK, and MnSOD levels in HDFs but not in HCT116 cells. Cellular ATP level was decreased only in HDFs by metformin. Metformin increased ROS level only in HCT116 cells. Transfection of si-FOXO3a into HCT116 reversed the metformin-induced cellular ROS induction, indicating that FOXO3a/MnSOD is the key regulator for cellular ROS level. Viability readout with M, E, and F alone decreased slightly, but the combination of three drugs dramatically decreased cell survival in HCT116, A549, and SK-Hep-1 cancer cells but not in HDF cells. ROS levels in HCT116 cells were massively increased by M + E + F combination, but not in HDF cells. Cell cycle analysis showed that of M + E + F combination caused cell death only in HCT116 cells. The combination of M + E + F reduced synergistically mitochondrial membrane potential and mitochondrial electron transport chain complex I and III activities in HCT116 cells when compared with individual treatments. Western blot analysis indicated that DNA damage, apoptosis, autophagy, and necroptosis-realated factors increased in M + E + F-treated HCT116 cells. Oral administration with M + E + F combination for 3 weeks caused dramatic reductions in tumor volume and weight in HCT116 xenograft model of nude mice when compared with untreated ones. Our results suggest that M + E + F have profound anticancer activity both and via a cancer cell-specific ROS amplification (CASRA) through ROS-induced DNA damage, apoptosis, autophagy, and necroptosis.
Topics: Animals; Mice; Humans; Metformin; Reactive Oxygen Species; Fluoxetine; AMP-Activated Protein Kinases; Mice, Nude; Signal Transduction; Apoptosis; HCT116 Cells; Cell Line, Tumor; Neoplasms
PubMed: 36588385
DOI: 10.1080/15384047.2022.2161803 -
World Journal of Gastroenterology Feb 2024Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.
AIM
To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET.
METHODS
A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival.
RESULTS
A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; < 0.001). The study heterogeneity was intermediate, with = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.
CONCLUSION
T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Neuroendocrine Tumors; Retrospective Studies; Pancreatic Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 38515954
DOI: 10.3748/wjg.v30.i7.759 -
Signal Transduction and Targeted Therapy Aug 2023The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the...
The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin's therapeutic efficacy in PCa.
Topics: Male; Humans; Metformin; Cell Line, Tumor; Prostatic Neoplasms; Transcription Factors; Cell Cycle
PubMed: 37582751
DOI: 10.1038/s41392-023-01516-2 -
Scientific Reports Aug 2023Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this... (Randomized Controlled Trial)
Randomized Controlled Trial
Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.
Topics: Humans; Female; Breast Neoplasms; Metformin; Ventricular Function, Left; Stroke Volume; Donepezil; Cardiotoxicity; Leukocytes, Mononuclear; Doxorubicin; Natriuretic Peptide, Brain; Peptide Fragments
PubMed: 37550350
DOI: 10.1038/s41598-023-40061-4 -
BMC Pulmonary Medicine Sep 2023Metformin is the most frequently prescribed medication for the treatment of type II diabetes mellitus and has played an anti-tumor potential in a variety of cancer...
BACKGROUND
Metformin is the most frequently prescribed medication for the treatment of type II diabetes mellitus and has played an anti-tumor potential in a variety of cancer types. Metformin can inhibit the growth of many cancer cells through various mechanisms, including ferroptosis. However, it is still unclear whether metformin can induce ferroptosis in lung cancer.
METHODS
This study evaluated the anti-tumor effect of metformin by detecting the levels of oxidative stress factors, the levels of ferrous ions, and the expression of ferroptosis-related genes in A549 and H1299 lung cancer cell lines treated with or without metformin.
RESULTS
The results showed that metformin treatment increased the levels of MDA, ROS and iron ions, while decreased the levels of GSH, T-SOD and CAT. Meanwhile, metformin treatment reduced the protein expression levels of Gpx4 and SLC7A11, Nrf2 and HO-1, while the addition of ferroptosis inhibitor ferrostatin-1 reversed the reduction.
CONCLUSIONS
These results demonstrated that metformin exerts anti-tumor effects by inducing ferroptosis through the Nrf2/HO-1 signaling pathway in lung cancer cells, providing a theoretical basis for drug therapy of lung cancer patients.
Topics: Humans; Ferroptosis; Lung Neoplasms; Metformin; NF-E2-Related Factor 2; Signal Transduction; Cell Line, Tumor
PubMed: 37749553
DOI: 10.1186/s12890-023-02655-6 -
Clinical and Experimental Medicine Nov 2023Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin... (Review)
Review
Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cutting-edge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Hypoglycemic Agents
PubMed: 37016064
DOI: 10.1007/s10238-023-01051-y -
Medicine Sep 2023Regarding the impact of metformin on COVID-19, there are currently varying opinions from multiple studies. Growth differentiation factor 15 (GDF-15) is a biomarker of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Regarding the impact of metformin on COVID-19, there are currently varying opinions from multiple studies. Growth differentiation factor 15 (GDF-15) is a biomarker of metformin use and dosage, and we used two-sample Mendelian randomization (MR) to assess the causal effect of GDF-15 (metformin) on COVID-19 susceptibility, hospitalization, and severe COVID-19, thereby guiding the selection of glucose-lowering agents for diabetic patients during the COVID-19 pandemic.
METHODS
Two sets of genetic tools were utilized for MR analysis, derived from publicly available genetic data. The first set was GDF-15 genome-wide association study (GWAS) data from a study with 5440 participants, while the second set was COVID-19 GWAS data from the Host Genetics Initiative (HGI) GWAS meta-analysis. The primary method used to assess causal effects was random effects inverse variance weighted estimation. Complementary methods included weighted median and MR-Egger analyses. Sensitivity analysis was performed using Cochran Q tests, MR-Egger intercept tests, MR-PRESSO, leave-one-out analyses, and funnel plots.
RESULTS
GDF-15 increased the risk of severe COVID-19 in patients (OR = 1.10, 95% CI 1.03-1.19; P = .006); there was no causal effect of GDF-15 on hospitalization for COVID-19 (OR = 1.02, 95% CI 0.96-1.07; P = .47) or susceptibility to COVID-19 in the general population (OR = 1.010, 95% CI 0.988-1.034; P = .354).
CONCLUSIONS
Our study supports the notion that GDF-15 increases the risk of severe COVID-19 in patients. However, there is no causal relationship between GDF-15 and hospitalization or susceptibility to COVID-19.
Topics: Humans; Biomarkers; COVID-19; Genome-Wide Association Study; Growth Differentiation Factor 15; Mendelian Randomization Analysis; Metformin; Pandemics
PubMed: 37773870
DOI: 10.1097/MD.0000000000034675 -
Journal of Translational Medicine Jul 2023Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell...
BACKGROUND
Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated.
METHODS
Tumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan-Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry.
RESULTS
Clinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin-a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes-reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin.
CONCLUSIONS
The current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.
Topics: Humans; Animals; Mice; Carcinoma, Squamous Cell; Mouth Neoplasms; Interleukin 1 Receptor Antagonist Protein; Squamous Cell Carcinoma of Head and Neck; Cisplatin; Diabetes Mellitus, Type 2; Cell Line, Tumor; Head and Neck Neoplasms; ErbB Receptors; Metformin; Cell Proliferation; Cell Movement; SOXB1 Transcription Factors
PubMed: 37461111
DOI: 10.1186/s12967-023-04343-9 -
The Journal of Clinical Endocrinology... Aug 2023Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade systemic inflammation and increased risk of pregnancy complications. Metformin...
CONTEXT
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade systemic inflammation and increased risk of pregnancy complications. Metformin treatment reduces the risk of late miscarriage and preterm birth in pregnant women with PCOS. Whether the protective effect of metformin involves immunological changes has not been determined.
OBJECTIVE
To investigate the effect of metformin on the maternal immunological status in women with PCOS.
METHODS
A post-hoc analysis was performed of two randomized controlled trials, PregMet and PregMet2, including longitudinal maternal serum samples from 615 women with PCOS. Women were randomized to metformin or placebo from first trimester to delivery. Twenty-two cytokines and C-reactive protein were measured in serum sampled at gestational weeks 5 to 12, 19, 32, and 36.
RESULTS
Metformin treatment was associated with higher serum levels of several multifunctional cytokines throughout pregnancy, with the strongest effect on eotaxin (P < .001), interleukin-17 (P = .03), and basic fibroblast growth factor (P = .04). Assessment of the combined cytokine development confirmed the impact of metformin on half of the 22 cytokines. The immunomodulating effect of metformin was more potent in normal weight and overweight women than in obese women. Moreover, normoandrogenic women had the strongest effect of metformin in early pregnancy, whereas hyperandrogenic women presented increasing effect throughout pregnancy.
CONCLUSION
It appears that metformin has immunomodulating rather than anti-inflammatory properties in pregnancy. Its effect on the serum levels of many multifunctional cytokines demonstrates robust, persisting, and body mass-dependent immune mobilization in pregnant women with PCOS.
Topics: Female; Pregnancy; Infant, Newborn; Humans; Metformin; Polycystic Ovary Syndrome; Hypoglycemic Agents; Pregnant Women; Premature Birth; Abortion, Spontaneous; Cytokines; Randomized Controlled Trials as Topic
PubMed: 36916886
DOI: 10.1210/clinem/dgad145 -
Cells Aug 2023The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic...
The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can improve other disease states, such as polycystic ovary disease, acute kidney injury, neurological disorders, cognitive impairment and renal damage. In addition, metformin is well known to suppress the growth and progression of different types of cancer cells both in vitro and in vivo. Accordingly, several epidemiological studies suggest that metformin is capable of lowering cancer risk and reducing the rate of cancer deaths among diabetic patients. The antitumoral effects of metformin have been proposed to be mainly mediated by the activation of the AMP-activated protein kinase (AMPK). However, a number of signaling pathways, both dependent and independent of AMPK activation, have been reported to be involved in metformin antitumoral action. Among these, the Wingless and Int signaling pathway have recently been included. Here, we will focus our attention on the main molecular mechanisms involved.
Topics: Female; Humans; Metformin; Wnt Signaling Pathway; AMP-Activated Protein Kinases; Diabetes Mellitus, Type 2; Neoplasms
PubMed: 37681914
DOI: 10.3390/cells12172182