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Open Life Sciences 2020Buformin has been reported to be a powerful anticancer drug by activating the AMPK signal. Herein, we aimed to investigate the effects of buformin on osteosarcoma.
BACKGROUND
Buformin has been reported to be a powerful anticancer drug by activating the AMPK signal. Herein, we aimed to investigate the effects of buformin on osteosarcoma.
MATERIAL AND METHODS
Cellular proliferative abilities were determined by cell counting kit-8 and colony formation assays. Cellular invasion was investigated using a transwell system. Cell cycle was examined by flow cytometry. Western blot was performed to measure the expression of key proteins. Synergistic effects of buformin and cisplatin were validated in seven fresh osteosarcoma tissues.
RESULTS
Buformin suppressed the growth of U-2 OS cells in a dose-dependent manner (IC50 = 69.1 µM). Moreover, buformin induced cell cycle arrest ( < 0.001) and impaired cellular invasion ( = 0.038). Phosphorylation of AMPK was upregulated by buformin, while phosphorylation of S6, cyclin D1, and MMP9 were significantly downregulated. In addition, buformin notably induced accumulation of reactive oxygen species and lactate and eventually decreased ATP production. In both U-2 OS cells and the primary cultured osteosarcoma tissues, buformin increased tumor sensitivity to cisplatin.
CONCLUSIONS
Buformin could suppress tumor growth and invasion of osteosarcoma through directly targeting the AMPK signaling pathway. Moreover, buformin inhibited the abnormal metabolism and notably increased the cytotoxicity of cisplatin, and therefore represents a new potential treatment option for osteosarcoma.
PubMed: 33817229
DOI: 10.1515/biol-2020-0041 -
World Academy of Sciences Journal May 2020The mammalian target of rapamycin (mTOR) signaling pathway senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate...
The mammalian target of rapamycin (mTOR) signaling pathway senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Rapamycin is a bacterial product that can inhibit mTOR via the PI3K/AKT/mTOR pathway. mTOR signaling is necessary for the development of influenza and modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. In one human study, it was found that the treatment of severe H1N1 influenza‑related pneumonia with rapamycin and steroids improved the outcome. However, in other studies, immunosuppression with systemic steroids, and possibly rapamycin as well, was associated with an increased morbidity/mortality and a prolonged viral replication. In order to avoid the systemic side-effects, some investigators have postulated that the inhalation of rapamycin would be desirable. However, the inhalation of rapamycin, with its well-documented lung toxicity, could be contraindicated. Another class of drug, biguanides, can also inhibit mTOR, but have no lung toxicity. Biguanides are widely used small molecule drugs prescribed as oral anti-diabetics that have exhibited considerable promise in oncology. During the 1971 outbreak of influenza, diabetic patients treated with the biguanides, phenformin and buformin, had a lower incidence of infection than diabetics treated with sulfonylureas or insulin. Both buformin and phenformin reduce the mortality of influenza in mice; phenformin is less effective than buformin. The inhalation of buformin or phenformin for influenza may be an effective novel treatment strategy that would limit the risk of systemic side-effects associated with biguanides due to the low inhaled dose. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a virus closely related to the SARS virus. The disease is the cause of the 2019-2020 coronavirus outbreak. It is primarily spread between individuals via small droplets emitted from infected individuals when breathing or coughing. PI3K/AKT/mTOR signaling responses play important roles in MERS-CoV infection and may represent a novel drug target for therapeutic intervention strategies. The present review article discusses the effects of biguanides on influenza and coronavirus.
PubMed: 32313883
DOI: 10.3892/wasj.2020.42 -
Cancers May 2022In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias' (AMLs) cells and described a heterogeneous and highly flexible...
In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias' (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate-buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.
PubMed: 35626170
DOI: 10.3390/cancers14102565 -
Biological & Pharmaceutical Bulletin 2022We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels...
We studied the effect of dietary fibers (DFs) on the levels of free hypoglycemic agents in vitro, i.e., glimepiride and the biguanides buformin and metformin. The levels of free buformin and free metformin were not affected by mixtures of DFs, i.e., cellulose, chitosan, pectin (PE), and glucomannan (GM), in fluids of pH 1.2 and 6.8 (similar to the pH of the stomach and intestines, respectively). However, the free biguanide level was significantly reduced by mixing with PE or sodium alginate (AL), in water. The free glimepiride level was reduced in the mixture of AL, PE, and GM (in a solution with a pH of 6.8). The changes in aqueous AL solution pH seemed to reflect the free metformin levels. Therefore, the effects of DFs on free drug levels were dependent on drug type, hypoglycemic agent, and mixing solution. In this study, the oral regimen concentrations of the drug and DFs were used. Based on these results, it is important to consider the interactions between hypoglycemic agents and DFs.
Topics: Hypoglycemic Agents; Buformin; Metformin; Dietary Fiber
PubMed: 36328507
DOI: 10.1248/bpb.b22-00385 -
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 -
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 -
RSC Advances Apr 2021A bar micro-solid phase (bar μ-SPE) extraction method using either graphene or zeolite or their mixtures as an adsorbent, coupled with high-performance liquid...
A bar micro-solid phase (bar μ-SPE) extraction method using either graphene or zeolite or their mixtures as an adsorbent, coupled with high-performance liquid chromatography (using a C1 column) was developed for the simultaneous determination of pharmaceutical compounds (metformin (MET), buformin (BUF), phenformin (PHEN) and propranolol (PROP)) of diverse polarity (log from -1.82 to 3.10). Parameters influencing the extraction, such as conditioning solvents, pH of the sample, sample volume, amount of adsorbent, stirring rate, time of extraction, type and volume of desorption solvent and time of desorption were investigated. Under the optimized conditions, the extraction method using graphene (extraction efficiency, % EE, ∼6-15%) resulted in the least amount of extracted drugs. However, the use of zeolite and zeolite/graphene mixtures improves the % EE significantly, 30% for PHEN and 42% for PROP using zeolite; 22% for MET and 18% for BUF using the adsorbent mixture. Under similar conditions, enrichment factors for these drugs range from 11-15. The validated method was performed for the determination of the drugs that were spiked to urine samples. Good recoveries ranging from 72.8 to 116% were achieved.
PubMed: 35479128
DOI: 10.1039/d1ra01569a -
IScience Feb 2024Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut...
Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (K) of agmatinase is 1 mM and relevant in the gut where the drug concentration is 1-10 mM. Metformin analogs phenformin, buformin, and galegine are even more potent inhibitors of agmatinase (K = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin's therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin's action in the gut and may lead to significant discoveries in improving metformin therapy.
PubMed: 38318350
DOI: 10.1016/j.isci.2024.108900