Drug Metformin Research Articles

Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact.

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.

<i>In Silico</i> Screening of a Phytochemical Naringin, Isolated from <i>Citrus decumana</i> var. <i>paradisi</i> Against the Genes of Polycystic Ovary Syndromenes of Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is a complex hormonal and metabolic disorder. The overproduction of androgens is the primary feature of PCOS. The currently available pharmacological agents recommended for the treatment of PCOS are linked with several adverse effects. Therefore, herbal-based drugs with lesser side effects, have become a favourable trend among people. A flavonoid glycoside, naringin isolated from different fruit parts of Citrus decumana var. paradisi (Macfad.) H.H.A. Nicholls exhibits a wide range of therapeutic properties. In the traditional system of medicine, it is used to improve ovarian health. To set down scientific evidence, molecular docking analysis was performed to find out the binding affinity of compound naringin with the protein CYP 17-cytochrome P 450, attributing to hyperandrogenism due to its overexpression, leading to PCOS. The docking score values were compared with the standard drug metformin to interpret the effectiveness of flavonoid naringin in the treatment of PCOS.

Unveiling the presence of insulin-like antidiabetic proteins in potato: A wholesome food

A study was taken up to explore the possibilities for the presence of Insulin like protein in potato tubers. The serological based Direct antigen coating-Enzyme linked immune sorbent assay (DAC-ELISA) clearly detected and quantified the presence of insulin like proteins in dormant and sprouted potato tubers. Presence of ILP was further confirmed in dormant or sprouted potato tuber by Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis where an expected size of approximately 10 kDa corresponding to that of Insulin standard was recorded. In the second phase, an in vivo antihyperglycemic activity was carried out by administering the lyophilized powder derived from the tubers of Indian potato varieties to streptozotocin-induced diabetic rats. Among the varieties, Kufri Surya and Kufri Pushkar reduced the blood sugar level to 29.7% and 18% respectively, whereas, the metformin drug reduced the blood sugar level to 23.6%. In addition, the antioxidant and antidiabetic compounds (other than insulin like proteins) of the same varieties were also studies where Kufri Surya was found to be rich in nutrients and antidiabetic compounds. This is the first report on presence of insulin like proteins in the tubers of Indian potato varieties. The study presents a lead to explore the genes expressing insulin like proteins and subsequent utilization in developing specialty insulin rich potato varieties either by biotechnological based gene transfer approaches or by traditional breeding approach.

A Review of Recent Advances in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed.As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

Synthesis and hypoglycemic activity of new nicotinonitrile-furan molecular hybrids

New hybrid molecules bearing 4-(2-furyl)-1,4-dihydronicotinonitrile and 4-(2-furyl)-1,4,5,6-tetrahydronico- tinonitrile fragments were prepared starting from cyanothioacetamide and furfural. The hypoglycemic activity in dexamethasone-induced diabetes mellitus was investigated in vivo in senile rats. Some compounds revealed hypoglycemic effects superior to that of the reference drug (metformin).

Exploiting of Green Synthesized Metal Oxide Nanoparticles in the Potentiometric Determination of Metformin Hydrochloride in Pharmaceutical Products.

The advanced and highly functional properties of Al2O3 and NiO nanoparticles promote the widespread use of metal oxides as remarkable electroactive materials for sensing and electrochemical applications. The proposed study describes a comparison of the sensitivity and selectivity of two modified wire membrane sensors enriched with Al2O3 and NiO nanoparticles with conventional wire membranes for the quantification of the antidiabetic drug metformin hydrochloride (MTF). The results show linear relationships of the enriched Al2O3 and NiO nanosensors over the concentration ranges 1.0 × 10-10-1.0 × 10-2 mol L-1 and 1.0 × 10-6-1.0 × 10-2 M for both the modified sensors and the conventional coated wire membrane sensors. The regression equations were EmV = (52.1 ± 0.5) log (MTF) + 729 for enriched nanometallic oxides, EmV = (57.04 ± 0.4) log (MTF) + 890.66, and EmV = (58.27 ± 0.7) log (MTF) + 843.27 with correlation coefficients of 0.9991, 0.9997, and 0.9998 for the aforementioned sensors, respectively. The proposed method was fully validated with respect to the recommendations of the International Union of Pure and Applied Chemistry (IUPAC). The newly functionalized sensors have been successfully used for the determination of MTF in its commercial products.

Development of chitosan lipid nanoparticles to alleviate the pharmacological activity of piperine in the management of cognitive deficit in diabetic rats

The aim of the present study was to prepare and evaluate Piperine (PP) loaded chitosan lipid nanoparticles (PP-CLNPs) to evaluate its biological activity alone or in combination with the antidiabetic drug Metformin (MET) in the management of cognitive deficit in diabetic rats. Piperine was successfully loaded on CLNPs prepared using chitosan, stearic acid, Tween 80 and Tripolyphosphate (TPP) at different concentrations. The developed CLNPs exhibited high entrapment efficiency that ranged from 85.12 to 97.41%, a particle size in the range of 59.56–414 nm and a negatively charged zeta potential values (− 20.1 to − 43.9 mV). In vitro release study revealed enhanced PP release from CLNPs compared to that from free PP suspensions for up to 24 h. In vivo studies revealed that treatment with the optimized PP-CLNPs formulation (F2) exerted a cognitive enhancing effect and ameliorated the oxidative stress associated with diabetes. PP-CLNPs acted as an effective bio-enhancer which increased the potency of metformin in protecting brain tissue from diabetes-induced neuroinflammation and memory deterioration. These results suggested that CLNPs could be a promising drug delivery system for encapsulating PP and thus can be used as an adjuvant therapy in the management of high-risk diabetic cognitive impairment conditions.

Antidiabetic action of the Chinese formula Shouhuitongbian and the underlying mechanism associated with alteration of gut microbiota

BackgroundThe prevalence and incidence of type 2 diabetes mellitus (T2DM) have dramatically increased. The intestinal flora and its derived metabolites are demonstrated to play vital roles in the etiology and onset of T2DM. Shouhuitongbian (SHTB) is a traditional Chinese formula to treat constipation. SHTB is composed of seven herbs and components of Colla corii asini (CCA) that are obtained from the hide of Equus asinus L.. Some of herbs in SHTB such as Aloe vera (L.) Burm.f., Cassia obtusifolia L., fruits of Lycium barbarum L., and Citrus aurantium L. have shown to improve insulin resistance (IR) and T2DM in early reports. We hypothesized that SHTB composed of these herbs has antidiabetic effects. The antidiabetic efficacy and mechanism of action of SHTB have not been previously reported. Hypothesis/PurposeTo demonstrate the antidiabetic effect and elucidate the underlying mechanisms of SHTB from the perspective of gut microbiota. Study designThe main compounds were identified and quantified by high-performance liquid chromatography (HPLC)-mass spectrometry analysis. High fat diet (HFD)-fed mice and db/db mice were used to assess the antidiabetic effects and the mechanism of SHTB. The underlying mechanisms were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot analysis, quantitative real time polymerase chain reaction (qPCR) analysis, 16S rRNA high-throughput sequencing, and targeted metabolome analysis. MethodsHFD-fed mice and db/db mice were orally treated with the standard positive drug metformin (100 mg/kg/d) and with SHTB (200 and 100 mg/kg/d), which was chemically characterized according to the European Medicine Agency (EMA) guidelines. The beneficial effects of SHTB were studied by homeostasis model assessment of insulin resistance (HOMA-IR) index, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), total cholesterol (T-CHO), triglyceride (TG), and inflammation. Subsequently, 16S rDNA-based high-throughput pyrosequencing and GC-MS-based targeted metabolomics profiling were performed to analyze the gut microbiota composition and metabolites profile in the gut, respectively. Moreover, the mammalian target of rapamycin complex 1 (mTORC1) / insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) pathway was evaluated via qPCR and western blot. ResultsChemically characterized SHTB, in which six markers were quantified, effectively alleviated glucose intolerance and IR, ameliorated lipid metabolism dysfunction, and reduced inflammation. In addition, 16S rDNA sequencing found that SHTB reshaped the composition of intestinal flora, as indicated by the enrichment of Akkermansia and Parabacteroides in both HFD-fed and db/db mice. Moreover, SHTB enhanced the intestinal production of short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BSCFAs), and reduced the levels of the fecal and circulating branched-chain amino acids (BCAAs). The IRS-1/PI3K/AKT signaling pathway was upregulated after treatment with SHTB. ConclusionOrally administration of SHTB effectively improved IR and reduced hyperglycemia in mice. Treatment with SHTB regulated the gut BCAAs-mTORC1/IRS-1/PI3K/AKT axis by enhancing the BCAAs catabolism in the gut, which attenuated the deleterious effect of BCAAs on the IRS-1 signaling pathway.

Metformin, Chlorpropamide, and Glibenclamide: Interactions with Metal Ions and Cyclodextrins

Abstract: In the field of Chemistry, it is essential to study molecules with biological activity on chronic degenerative diseases to design drugs that help to improve the health of people with diseases such as diabetes, arterial hypertension, rheumatoid arthritis, cancer, among others; and that in turn may have fewer side effects. Diabetes mellitus is a serious metabolic disorder that affects millions of people worldwide; due to the illness severe affectations, there is a great interest in improving pharmacological treatments (hypoglycemic drugs) used in this disease. Nowadays, it has been reported that metallodrugs and drug-cyclodextrin inclusion compounds have higher therapeutic activity than free drugs, with fewer side effects. In the present work, we compile, analyze, synthesize and discuss published information on the hypoglycemic drugs Metformin (C4H11N5), Chlorpropamide (C10H13ClN2O3S) and Glibenclamide (C23H28ClN3O5S) complexed with metal ions or included in cyclodextrins in aqueous solution. Nowadays, this type of complex should be widely studied for the treatment of type 2 diabetes mellitus. Physicochemical and thermodynamic properties, synthesis, mechanism of action, as well as analytical studies on the interaction of hypoglycemic agents with different complexing agents, are discussed.

Evaluation of the Neuroprotective Action of <i>Azadirachta indica</i> Leaves Extract in Streptozotocin-induced Diabetic Rodent Model

Among the most common and painful consequences of diabetes mellitus, Diabetic Peripheral Neuropathy (DPN) is one of the most common. For DPN management, a variety of techniques have been used, ranging from traditional medicines to alternative approaches. Natural compounds are also the focus of research to explore the possible treatment by replacing or combining with the existing therapies. Different neurological changes in diabetic neuropathy and the effect of the Azadirachta indica (neem) extract were assessed with nerve conduction velocity, and biochemical and histological analysis in Streptozotocin-induced diabetic mellitus. The therapeutic effect of the extract was evaluated with doses 100, 200 and 500mg/kg body weight for 4 weeks after induction of diabetes. The protective effect was evaluated by treating the animals with hydroalcoholic extract of neem leaves in 500mg/kg dose before the induction of diabetes and post-treatment with the standard drug Metformin (500mg/kg). Both resulted in a significant reduction in blood glucose, additionally, 500mg/kg body weight dose revealed the signs of neuroprotection in diabetic rats. Neem leaf extract appears to be promising for future investigations, which might contribute to the emergence of new drugs for diabetes treatment and diabetic neuropathy either alone or in combination with conventional therapies.

Use of a renal OCT2/Mate biomarker (N1-methylnicotinamide) to enable the early clinical assessment of metformin drug interaction potential

Use of a renal OCT2/Mate biomarker (N1-methylnicotinamide) to enable the early clinical assessment of metformin drug interaction potential

Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment

BackgroundCombining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there...

Invitro evaluation of generic vs branded product of metformin tablet

The main aim and objective of present research work is to evaluate and compare the standards concerning quality of generic and branded anti hyperglycemic drug (Metformin Hcl). Metformin tablets are evaluated as per standard protocol and results shows that branded and generic meets the pharmacopoeial specifications. All tablets passed the test of weight variation, hardness, thickeness, friability, disintegration, dissolution and assay as per Indian pharmacopoeia. Both the generic and branded tablets of metformin shows similar results. So, health care professionals are suggested to prescribe generic drug so, that everyone can reach the cost of the drug and maintain good health.

Trace Level Quantification of Genotoxic Impurities through Atmospheric Pressure Chemical Ionization (APCI) Coupled with Triple Quardrapole Analyzer in Combination Diabetic Drug Product

N-Nitrosamine impurities have been found in several drug products, showing a concern for regulatory aspects. The study presents the development and validation of a sensitive LC-MS/MS method for detecting eight nitrosamines in vildagliptin and metformin drug products. The developed method was specific and linearity was ranged 3.53-55.92 ppb for NDMA, 3.18-50.37 ppb for NMBA, 0.97-15.41 ppb for NDEA, 0.98-15.52 ppb for NEIPA, 1.00-15.86 ppb for NDIPA, 0.98-15.46 ppb for NDBA, 0.98-15.58 ppb for NMPA and 0.7-15.32 ppb for NDPA with correlation coefficient (r) was more than 0.98 and square of correlation coefficient (r2) was found to be greater than 0.96. The LOQ were obtained in the range of 0.97-3.53 ppb with %RSD in the range of 2.5-10.9% for eight nitrosamines showed good sensitivity. Accuracy was found in the range of 98.63 ± 5.77-125.17 ± 3.68% at LOQ level, 74.77 ± 0.83-88.17 ± 0.15% at 50% level, 79.93 ± 8.47-89.00 ± 0.61% at 100% level and 74.67 ± 2.31-84.03 ± 0.93% at 150% level for the eight nitrosamine impurities that were well within acceptance criteria of not less than 70% and not more than 130%. The method validation results demonstrated that the method is precise, accurate and linear, can be applied to quantify the nitrosamines in vildagliptin and metformin drug products.

Modulating the antibacterial effect of the existing antibiotics along with repurposing drug metformin.

Owing to the extensive prevalence of resistant bacteria to numerous antibiotic classes, antimicrobial resistance (AMR) poses a well-known hazard to world health. As an alternate approach in the field of antimicrobial drug discovery, repurposing the available medications which are also called antibiotic resistance breakers has been pursued for the treatment of infections with antimicrobial resistance pathogens. In this study, we used Haloperidol, Metformin and Hydroxychloroquine as repurposing drugs in in vitro (Antibacterial Antibiotic Sensitivity Test and Minimum Inhibitory Concentration-MIC) and in vivo (Shigellosis in Swiss albino mice) tests in combination with traditional antibiotics (Oxytetracycline, Erythromycin, Doxycycline, Gentamicin, Ampicillin, Chloramphenicol, and Penicillin) against a group of AMR resistance bacteria (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Shigella boydii). After observing the results of the conducted in vitro experiments we studied the effects of the above non antibiotic drugs in combination with the said antibiotics. As an repurposing adjuvant antibiotic drug, Metformin exhibited noteworthy activity in almost all in vitro, in vivo and in silico tests (Zone of inhibition for 30 to 43mm for E.coli in combination with Doxycycline; MIC value decreased 50 µM to 0.781 µM with Doxycycline on S. boydii).In rodents Doxycycline and Metformin showed prominent against Shigellosis in White blood cell count (6.47 ± 0.152 thousand/mm3) and Erythrocyte sedimentation rate (10.5 ± 1.73mm/hr). Our findings indicated that Metformin and Doxycycline combination has a crucial impact on Shigellosis. The molecular docking study was performed targeting the Acriflavine resistance protein B (AcrB) (PDB ID: 4CDI) and MexA protein (PDB ID: 6IOK) protein with Metformin (met8) drug which showed the highest binding energy with - 6.4kcal/mol and - 5.5kcal/mol respectively. Further, molecular dynamics simulation revealed that the docked complexes were relatively stable during the 100 ns simulation period. This study suggest Metformin and other experimented drugs can be used as adjuvants boost up antibiosis but further study is needed to find out the safety and efficacy of this non-antibiotic drug as potent antibiotic adjuvant.

Sol-gel synthesis, physicochemical characteristics and in vitro pH-responsive metformin drug release of uniformly polydopamine coated mesoporous silica nanospheres

A recent attention has been paid to the repurposing potential of metformin drug for cancer chemotherapy. Herein, pH-responsive metformin drug delivery nanocarriers were achieved using sol-gel synthesized mesoporous silica nanospheres (MSN) uniformly coated with polydopamine (PDA) shell. The PDA coating shell around the MSN surface was in situ formed through oxidative self-polymerization of dopamine monomers in an alkaline solution at room temperature. The microstructure, structural and textural characteristics of PDA@MSN were examined and compared to uncoated MSN. Furthermore, PDA coated metformin (MET) drug-loaded MSN were used to study the pH-responsive MET drug release behaviour under neutral and acidic conditions. The in vitro release test showed that the PDA coating shell not only protects MET drug leakage under normal physiological conditions (pH 7.4) but also allows for its controlled/sustained release in acidic conditions (pH 4.5 and pH 5.5) which closely mimic the intracellular acidity (pH 4.5–5.5) of endosomes/lysosomes formed around drug-loaded nanocarriers after their endocytosis by cancer cells.

Abstract 4053: Targeting oxygen consumption with metformin and phenformin have differential effects on immune cells in the tumor microenvironment

Abstract T cell immune checkpoint blockade (ICB) has shown remarkable promise in melanoma and other cancers. However, most patients do not show clinical benefit. This is because tumors can activate multiple checkpoints and immunosuppressive pathways to evade anti-tumor immune responses. Inhibition of these immune suppressive mechanisms and immune checkpoints or repolarizing the tumor microenvironment (TME) to become more accessible to the immune system may be necessary for maximal therapeutic efficacy of immunotherapies. There is increasing evidence that tumor hypoxia can attenuate the antitumor immune response by promoting immune suppression and inhibiting direct killing by cytotoxic immune cells. We propose that blocking tumor oxygen consumption using drugs that target the mitochondrial complex I (phenformin and metformin) will enhance the efficacy of immunotherapies such as ICB in preclinical models such as B16 melanoma. In this study, we examined how low oxygen levels (hypoxia) influence T cell effector function such as cytotoxic activity and cytokine production in vitro. We co-cultured B16 melanoma cells in the presence of tumor specific T cells (Pmels) and incubated at 37ºC in either normoxia (~21% O2) or hypoxia (3% O2) and assessed killing and intracellular cytokine production 24 - 48 hours later. We show that the ability of tumor antigen-specific T cells to kill tumor cells or make effector cytokine such as IFNγ and TNFα is significantly reduced in hypoxia settings. We also examined the effects of hypoxia targeting drugs (metformin and phenformin) on T cell priming and activation. When T cells were activated in the presence of each drug in vitro, there was enhanced expression of T cell activation markers (CD25, Granzyme B) as well as an increase in their differentiation into central memory T cells. We next determined whether these drugs could alter the TME in vivo by treating C56BL/6J mice bearing established B16 tumors with phenformin and metformin and then examine the effects on the immune system in the tumor, tumor draining lymph nodes and spleen by flow cytometry. We found that these three drugs have differential effects on both the innate and adaptive the immune system in the tumors and periphery. Finally, we tested whether these drugs could delay B16 melanoma growth in vivo as a monotherapy or in combination with anti-PD1. We found that while both drugs can significantly delay tumor growth as monotherapies, only metformin showed improved anti-tumor efficacy when combined with anti-PD-1 in vivo. These studies show that while both drugs target tumor oxygen consumption (via inhibition of complex I), and can delay B16 tumor growth in vivo, they have differential effects on the TME and will need further considerations when combining with immune based therapies such as ICBs. Citation Format: Sadna Budhu, Anais Assouvie, Mamadou Bah, Svena Verma, Inna Serganova, Mayuresh Mane, Juan Zurita, Jason Koutcher, Vladimir Ponomarev, Jedd D. Wolchok, Taha Merghoub. Targeting oxygen consumption with metformin and phenformin have differential effects on immune cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4053.

Abstract 954: An evaluation of the combination of metformin and Y15 for the treatment of platinum-resistant ovarian cancer

Abstract Ovarian cancer is the fifth leading cause of cancer mortality among women. This high mortality rate is linked to the development of resistance to first-line chemotherapy with platinum compounds which has been attributed in part to increased activity of focal adhesion kinase (FAK). The anti-diabetic drug Metformin was previously shown to inhibit the proliferation and migration of ovarian cancer cells and thus, the combination of a FAK inhibitor, Y15, and Metformin may be a promising treatment for platinum-resistant ovarian cancer (PROC). The objective of this study was to evaluate the combination of Y15 and Metformin on PROC cell viability and the mechanism of cell death. An MTT assay was used to analyze cell viability in PROC OVCAR3 cells after 48 h of treatment by measuring the absorbance at 570 nm with a microplate reader. Western blot was used to determine the protein levels of the apoptosis marker cleaved PARP and the autophagy marker LC3B-II. The exposure of OVCAR3 platinum-resistant ovarian cancer cells to Metformin (4.5 mM) + Y15 (5.5 µM) resulted in a significantly enhanced cytotoxicity (32.6 ± 1.8%) compared to single drug treatment with either Metformin (4.5 mM) (65.0 ± 4.2%) or Y15 (5.5 µM) (66.0 ± 4.8%). A combination of Metformin (7.8 mM) + Y15 (5.5 µM) also resulted in a significantly enhanced cytotoxicity (22.8 ± 1.5%) compared to single drug treatment with either Metformin (7.8 mM) (50.7 ± 3.7%) or Y15 (5.5 µM) (66.0 ± 4.8%). Cells treated with the combination of Metformin and Y15 for 24, 48, and 72-hours showed an increase in cleaved PARP compared to the control, Metformin alone and Y15 alone. For Metformin alone, there was an increase in cleaved PARP compared to the control at all timepoints and increased from 24 hours to 72 hours. For Y15 alone, the amount of cleaved PARP was also higher compared to the control at all time points, however, decreased over time from 24 hours to 72 hours. Cells treated with Metformin, Y15, and a combination of Metformin and Y15 showed no conversion of LC3B-I to LC3B-II, which occurs during autophagy. Thus, it is concluded that the mechanism of cell death for both Metformin and Y15 is through apoptosis and not autophagy and apoptosis is enhanced with the combination of the drugs. The delivery of Metformin and Y15 can result in an additive effect on cell viability through apoptosis and can be further explored as a promising approach for the treatment of PROC. Citation Format: Manuel A. Duarte, Kristal Garcia, Marco A. Arriaga, Sue Anne Chew, Arkene S. Levy, Isabela Mendez. An evaluation of the combination of metformin and Y15 for the treatment of platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 954.

Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies.

Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin's anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment.

Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice

Mitochondrial dysfunction in pancreatic β-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment’s effects on mQC in diabetic β-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic β-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db β-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db β-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced β-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving β-cell function and effective glycemic control in T2D.