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The Journal of Clinical Endocrinology... Aug 2019Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset...
CONTEXT
Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients are resistant or poorly responsive to the main current medical treatments [i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists]. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known.
OBJECTIVE
We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion.
DESIGN
A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways.
RESULTS
Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type-specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms.
CONCLUSION
Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Biguanides; Cell Line, Tumor; Cell Survival; Humans; Hypoglycemic Agents; Neuroendocrine Tumors; Pituitary Neoplasms; Signal Transduction
PubMed: 30860580
DOI: 10.1210/jc.2019-00056 -
Scientific Reports Mar 2021To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural...
To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1- and unfolded protein response (UPR)-dependent reporter assays and selective cytotoxicity assay under low glucose conditions. Homologation studies of aryl-(CH)-biguanides (n = 0-6) yielded highly potent derivatives with an appropriate alkylene linker length (n = 5, 6). The o-chlorophenyl derivative 7l (n = 5) indicated the most potent inhibitory effects on HIF-1- and UPR-mediated transcriptional activation (IC; 1.0 ± 0.1 μM, 7.5 ± 0.1 μM, respectively) and exhibited selective cytotoxicity toward HT29 cells under low glucose condition (IC; 1.9 ± 0.1 μM). Additionally, the protein expression of HIF-1α induced by hypoxia and of GRP78 and GRP94 induced by glucose starvation was markedly suppressed by the biguanides, thereby inhibiting angiogenesis. Metabolic flux and fluorescence-activated cell sorting analyses of tumor cells revealed that the biguanides strongly inhibited oxidative phosphorylation and activated compensative glycolysis in the presence of glucose, whereas both were strongly suppressed in the absence of glucose, resulting in cellular energy depletion and apoptosis. These findings suggest that the pleiotropic effects of these biguanides may contribute to more selective and effective killing of cancer cells due to the suppression of various stress adaptation systems in the tumor microenvironment.
Topics: A549 Cells; Animals; Antineoplastic Agents; Biguanides; Chickens; Energy Metabolism; HEK293 Cells; HT29 Cells; Humans; Neoplasm Proteins; Neoplasms; Stress, Physiological; Tumor Microenvironment
PubMed: 33649449
DOI: 10.1038/s41598-021-83708-w -
International Wound Journal Dec 2012The TIME acronym (tissue, infection/inflammation, moisture balance and edge of wound) was first developed more than 10 years ago, by an international group of wound... (Review)
Review
The TIME acronym (tissue, infection/inflammation, moisture balance and edge of wound) was first developed more than 10 years ago, by an international group of wound healing experts, to provide a framework for a structured approach to wound bed preparation; a basis for optimising the management of open chronic wounds healing by secondary intention. However, it should be recognised that the TIME principles are only a part of the systematic and holistic evaluation of each patient at every wound assessment. This review, prepared by the International Wound Infection Institute, examines how new data and evidence generated in the intervening decade affects the original concepts of TIME, and how it is translated into current best practice. Four developments stand out: recognition of the importance of biofilms (and the need for a simple diagnostic), use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy as dressings and for wound lavage (notably, silver and polyhexamethylene biguanide) and expanded insight of the role of molecular biological processes in chronic wounds (with emerging diagnostics and theranostics). Tissue: a major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing, both in time-honoured and novel methods (notably using NPWT and hydrosurgery). Infection/inflammation: clinical recognition of infection (and non infective causes of persisting inflammation) is critical. The concept of a bacterial continuum through contamination, colonisation and infection is now widely accepted, together with the understanding of biofilm presence. There has been a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: the relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance, and to protect peri-wound skin, and optimise healing. Edge of wound: several treatment modalities are being investigated and introduced to improve epithelial advancement, which can be regarded as the clearest sign of wound healing. The TIME principle remains relevant 10 years on, with continuing important developments that incorporate new evidence for wound care.
Topics: Abbreviations as Topic; Anti-Bacterial Agents; Anti-Infective Agents, Local; Anxiety; Bandages; Biguanides; Biofilms; Debridement; Disinfectants; Disinfection; Drug Resistance, Bacterial; Electromagnetic Fields; Exudates and Transudates; Honey; Humans; Hyperbaric Oxygenation; Infections; Inflammation; Iodophors; Laser Therapy; Negative-Pressure Wound Therapy; Oxygen Inhalation Therapy; Pain Management; Silver Compounds; Silver Sulfadiazine; Stress, Psychological; Ultrasonic Therapy; Wound Healing; Wounds and Injuries
PubMed: 23145905
DOI: 10.1111/j.1742-481X.2012.01097.x -
International Journal of Cancer Mar 2015The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide...
The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence.
Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Electron Transport Complex I; Female; Humans; Metformin; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Phenformin; Phosphorylation; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 25196138
DOI: 10.1002/ijc.29193 -
Endocrinology and Metabolism Clinics of... Dec 2013Current strategies for the treatment of type 2 diabetes mellitus promote individualized plans to achieve target glucose levels on a patient-by-patient basis while... (Review)
Review
Current strategies for the treatment of type 2 diabetes mellitus promote individualized plans to achieve target glucose levels on a patient-by-patient basis while minimizing treatment related risks. Maintaining glycemic control over time is a significant challenge because of the progressive nature of diabetes as a result of declining β-cell function. This article identifies complications of non-insulin treatments for diabetes. The major classes of medications are reviewed with special focus on target population, mechanism of action, effect on weight, cardiovascular outcomes and additional class-specific side effects including effects on bone. Effects on β-cell function are also highlighted.
Topics: Biguanides; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Sulfonylurea Compounds; Thiazolidinediones
PubMed: 24286957
DOI: 10.1016/j.ecl.2013.06.005 -
JAMA Psychiatry Apr 2019Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the...
Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness.
IMPORTANCE
Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the opportunity to evaluate the potential for currently used medication to benefit people with serious mental illness (SMI).
OBJECTIVE
To determine whether hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs), L-type calcium channel (LTCC) antagonists, and biguanides are associated with reduced psychiatric hospitalization and self-harm in individuals with SMI.
DESIGN, SETTING, AND PARTICIPANTS
These within-individual cohort studies of patients with SMI compared rates of psychiatric hospitalization and self-harm during periods of exposure and nonexposure to the study drugs, with adjusting for a number of time-varying covariates. Participants included 142 691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia, or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. Data were analyzed from April 1 through August 31, 2018.
INTERVENTIONS
Treatment with HMG-CoA RIs, LTCC antagonists, or biguanides.
MAIN OUTCOMES AND MEASURES
Psychiatric hospitalizations and self-harm admissions.
RESULTS
Among the 142 691 eligible participants, the HMG-CoA RI exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.89; P < .001), schizophrenia (aHR, 0.75; 95% CI, 0.71-0.79; P < .001), and NAP (aHR, 0.80; 95% CI, 0.75-0.85; P < .001) and reduced self-harm rates in BPD (aHR, 0.76; 95% CI, 0.66-0.86; P < .001) and schizophrenia (aHR, 0.58; 95% CI, 0.45-0.74; P < .001). Exposure to LTCC antagonists was associated with reduced rates of psychiatric hospitalization and self-harm in subgroups with BPD (aHRs, 0.92 [95% CI, 0.88-0.96; P < .001] and 0.81 [95% CI, 0.68-0.95; P = .01], respectively), schizophrenia (aHRs, 0.80 [95% CI, 0.74-0.85; P < .001] and 0.30 [95% CI, 0.18-0.48; P < .001], respectively), and NAP (aHRs, 0.89 [95% CI, 0.83-0.96; P = .002] and 0.56 [95% CI, 0.42-0.74; P < .001], respectively). During biguanide exposure, psychiatric hospitalization rates were reduced in subgroups with BPD (aHR, 0.80; 95% CI, 0.77-0.84; P < .001), schizophrenia (aHR, 0.73; 95% CI, 0.69-0.77; P < .001), and NAP (aHR, 0.85; 95% CI, 0.79-0.92; P < .001), and self-harm was reduced in BPD (aHR, 0.73; 95% CI, 0.62-0.84; P < .001) and schizophrenia (aHR, 0.64; 95% CI, 0.48-0.85; P < .001).
CONCLUSIONS AND RELEVANCE
This study provides additional evidence that exposure to HMG-CoA RIs, LTCC antagonists, and biguanides might lead to improved outcomes for individuals with SMI. Given the well-known adverse event profiles of these agents, they should be further investigated as repurposed agents for psychiatric symptoms.
Topics: Biguanides; Bipolar Disorder; Calcium Channel Blockers; Female; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Psychotic Disorders; Registries; Schizophrenia; Schizophrenic Psychology; Self-Injurious Behavior; Sweden
PubMed: 30624557
DOI: 10.1001/jamapsychiatry.2018.3907 -
International Journal of Environmental... Mar 2023Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration...
Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32-1.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75-8.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91-7.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.
Topics: Male; Humans; Female; Aged; Aged, 80 and over; Biguanides; Acidosis, Lactic; Retrospective Studies; Metformin; Cohort Studies; Japan; Diabetes Mellitus; Inpatients
PubMed: 37047916
DOI: 10.3390/ijerph20075300 -
Medicina Intensiva Oct 2010Metformin is an oral biguanide widely used in the management of patients with type 2 diabetes. It produces non-specific gastrointestinal symptoms in 10-30% of the...
Metformin is an oral biguanide widely used in the management of patients with type 2 diabetes. It produces non-specific gastrointestinal symptoms in 10-30% of the patients. Lactic acidosis is the most serious side effect, so it must not be administered to patients with renal, liver, or heart insufficiency. Only a few cases of hepatotoxicity due to this drug have been documented. We report the case of a patient with type 2 diabetes mellitus and recent use of metformin who developed serious liver injury, followed by a favorable evolution.
Topics: Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Hypoglycemic Agents; Metformin
PubMed: 20045581
DOI: 10.1016/j.medin.2009.10.006 -
CMAJ : Canadian Medical Association... Jan 2005Diabetes mellitus is a chronic disease that is growing in prevalence worldwide. Pharmacologic therapy is often necessary to achieve optimal glycemic control in the... (Review)
Review
Diabetes mellitus is a chronic disease that is growing in prevalence worldwide. Pharmacologic therapy is often necessary to achieve optimal glycemic control in the management of diabetes. Orally administered antihyperglycemic agents (OHAs) can be used either alone or in combination with other OHAs or insulin. The number of available OHAs has increased significantly in the last decade, which translates into more therapeutic options and complex decision-making for physicians. This review article is designed to help with these decisions. We review the mechanism of action, efficacy and side effects of the different classes of OHAs (alpha-glucosidase inhibitors, biguanides, insulin secretagogues, insulin sensitizers and intestinal lipase inhibitor) and discuss the current recommendations for their use.
Topics: Acarbose; Administration, Oral; Biguanides; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Hypoglycemic Agents; Lipase; Sulfonylurea Compounds
PubMed: 15655244
DOI: 10.1503/cmaj.1031414 -
International Journal of Molecular... Jul 2019Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as... (Review)
Review
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Models, Biological; Neoplasms; Phenformin; Risk Factors
PubMed: 31284513
DOI: 10.3390/ijms20133316