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Virulence 2018Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and...
Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.
Topics: Amphotericin B; Antifungal Agents; Biguanides; Candida; Candida glabrata; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Lipopeptides; Metformin; Micafungin; Microbial Sensitivity Tests; Mycoses; TOR Serine-Threonine Kinases; Voriconazole
PubMed: 29962263
DOI: 10.1080/21505594.2018.1475798 -
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 -
The Biochemical Journal Sep 2014The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of...
The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.
Topics: Animals; Antimalarials; Antineoplastic Agents; Biguanides; Cattle; Diabetes Mellitus, Type 2; Electron Transport Complex I; Hep G2 Cells; Humans; Metformin; Mitochondria, Heart; Mitochondria, Liver; Mitochondrial Proton-Translocating ATPases; Oxidative Phosphorylation; Plasmodium; Proguanil; Rats; Reperfusion Injury; Triazines
PubMed: 25017630
DOI: 10.1042/BJ20140620 -
Biological & Pharmaceutical Bulletin May 2006The biguanides metformin and buformin, which are clinically used for diabetes mellitus, are known to improve resistance to insulin in patients. Biguanides were reported...
The biguanides metformin and buformin, which are clinically used for diabetes mellitus, are known to improve resistance to insulin in patients. Biguanides were reported to cause lactic acidosis as a side effect. Since the mechanism of the side effect still remains obscure, we have examined genes whose expression changes by treating HepG2 cells with buformin in order to elucidate the mechanisms of the side effect. A subtraction cDNA library was constructed by the method of suppressive subtractive hybridization and the screening of the library was performed with cDNA probes prepared from HepG2 cells treated with or without buformin for 12 h. The expression of the gene and the protein obtained by the screening was monitored by real-time RT-PCR with specific primers and Western blotting with specific antibody. The amounts of ATP and NAD+ were determined with luciferase and alcohol dehydrogenase, respectively. We found that expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPD) gene was suppressed by treating HepG2 cells with 0.25 mM buformin for 12 h as a result of the library screening. The decrease in the expression depended on the treatment period. The amount of GAPD protein also decreased simultaneously with the suppression of the gene expression by the treatment with buformin. The amount of ATP and NAD+ in the HepG2 cells treated with buformin decreased to 10 and 20% of the control, respectively. These observations imply that the biguanide causes deactivation of the glycolytic pathway and subsequently the accumulation of pyruvate and NADH and a decrease in NAD+. Therefore, the reaction equilibrium catalyzed by lactate dehydrogenase leans towards lactate production and this may result in lactic acidosis.
Topics: Acidosis, Lactic; Adenosine Triphosphate; Blotting, Western; Buformin; Cell Line; DNA, Complementary; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Hypoglycemic Agents; NAD; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 16651735
DOI: 10.1248/bpb.29.1006 -
Cancer Prevention Research... Jun 2015Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential...
Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.
Topics: Animals; Apoptosis; Blotting, Western; Buformin; Carcinogens; Cell Proliferation; Cell Transformation, Neoplastic; Female; Hypoglycemic Agents; Mammary Neoplasms, Experimental; Metformin; Phenformin; Rats; Rats, Sprague-Dawley
PubMed: 25804611
DOI: 10.1158/1940-6207.CAPR-14-0121 -
Experimental Biology and Medicine... Oct 2018Our idea originated in the thought of discovering new effects of old drugs. Although this study is a basic research, it is very close to clinical treatment. Flow...
Our idea originated in the thought of discovering new effects of old drugs. Although this study is a basic research, it is very close to clinical treatment. Flow cytometry and immunofluorescence were used to verify that buformin increases radiosensitivity. We aimed to address one of the thorniest problems in treatment process. Based on discovering new effects of old drugs, it is feasible to use buformin as an anticancer drug in clinical application. This will provide new ideas for clinical treatment.
PubMed: 32459508
DOI: 10.1177/1535370218813320 -
Scientific Reports May 2016Renal cell carcinomas (RCC) have two types of cells for carbon metabolism and for cell signaling under nutrient-deprivation conditions, namely starvation-resistant and...
Renal cell carcinomas (RCC) have two types of cells for carbon metabolism and for cell signaling under nutrient-deprivation conditions, namely starvation-resistant and starvation-sensitive cells. Here, we evaluated the mitochondrial characteristics of these cell types and found that the resistant type possessed higher activities for both mitochondrial oxidative phosphorylation and glycolysis than the sensitive types. These higher activities were supported by the stored carbon, lipid and carbohydrate sources, and by a low level of mitochondrial reactive oxygen species (ROS) due to sustained SOD2 expression in the resistant RCC cells. In metastatic RCC cases, higher SOD2 expression was associated with a significantly shorter survival period. We found that treatment with the drugs etomoxir and buformin significantly reduced mitochondrial oxidative phosphorylation and induced cell death under glucose-deprivation conditions in starvation-resistant RCC cells. Our data suggest that inhibitory targeting of mitochondria might offer an effective therapeutic option for metastatic RCC that is resistant to current treatments.
Topics: Acids; Buformin; Carcinoma, Renal Cell; Cell Death; Cell Line, Tumor; Epoxy Compounds; Flow Cytometry; Glycolysis; Humans; Kidney Neoplasms; Kinetics; Lipids; Mitochondria; Neoplasm Metastasis; Oxidative Phosphorylation; Oxygen Consumption; Prognosis; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 27157976
DOI: 10.1038/srep25669 -
International Journal of Molecular... Mar 2023Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein...
Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin's anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.
Topics: Humans; Metformin; Molecular Docking Simulation; Creatine; Biguanides; AMP-Activated Protein Kinases; Buformin; Neoplasms; Antimalarials
PubMed: 36982390
DOI: 10.3390/ijms24065316 -
Oncotarget Nov 2015During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available...
During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides.
Topics: Animals; Anticarcinogenic Agents; Cricetinae; Disease Models, Animal; Drug Administration Routes; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Metformin; Mice; Neoplasms; Rats; Species Specificity; Treatment Outcome
PubMed: 26583576
DOI: 10.18632/oncotarget.6347 -
Biological & Pharmaceutical Bulletin May 2006Aquaporin 3 (AQP3), a membrane protein, is known to permeabilize water and other small molecules such as glycerol and urea and is localized in the bowel, skin, kidney,...
Aquaporin 3 (AQP3), a membrane protein, is known to permeabilize water and other small molecules such as glycerol and urea and is localized in the bowel, skin, kidney, and erythrocytes. Since glycerol is a nutrient and serves as a source material in glycolytic metabolism, absorption of glycerol in the gastrointestinal tract may be under some control. Therefore we first investigated whether insulin regulating the glycolytic pathway took part in glycerol transport through AQP3 in the gastrointestinal tract and found that insulin significantly suppressed mRNA and protein expressions of AQP3 in Caco-2 cells. The antidiabetic drugs troglitazone and tolbutamide were also observed to suppress significantly AQP3 expression, but the biguanides metformin and buformin did not induce such suppression. Epinephrine was found to increase expression of AQP3, although glucagon showed no change of expression. Wortmannin and rapamycin were demonstrated to deactivate suppression of AQP3 expression by insulin and troglitazone, suggesting that the signal transducers, phosphoinositide 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), are involved in the signal pathway for regulating transcription of AQP3.
Topics: Actins; Androstadienes; Aquaporin 3; Biguanides; Blood Glucose; Blotting, Western; Caco-2 Cells; Chromans; Epinephrine; Gene Expression; Glucagon; Humans; Hypoglycemic Agents; Insulin; Insulin Antagonists; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thiazolidinediones; Tolbutamide; Troglitazone; Wortmannin
PubMed: 16651733
DOI: 10.1248/bpb.29.991