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Metformin is one of the most commonly prescribed medications for the treatment of type 2 diabetes. Numerous reports have suggested potential anti-cancerous and cancer preventive properties of metformin, although these findings vary depending on the intrinsic properties of the tumor, as well as the systemic physiology of patients. These intriguing s...
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Citations
... Metformin is a biguanide drug, first synthesized in 1922 by Werner & Bell from a plant called Galega officinalis (21). Associated with its anti-hyperglycemic action, low cost, and tolerance (low risk of lactic acidosis), metformin is considered the first-line therapy for T2DM patients (22). In 2005, Evans et al. published an innovative study, that highlighted for the first time the potential antitumoral effects of metformin by the demonstration that T2DM patients under metformin use have a lower risk of developing cancer compared to other diabetic patients that not used metformin (23). ...
... As a result of ATP depletion, metformin activates AMPK to restore energy homeostasis, leading to a change from anabolic to catabolic status, impairing the synthesis of proteins, lipids, and nucleotides, important for cancer growth (3,22). Although AMPK is directly activated as a consequence of ATP depletion, AMPK can be activated indirectly by the liver kinase B1 (LKB1), an upstream kinase that promotes AMPK activation through the phosphorylation of alpha (α) AMPK subunit, and through lysosomal pathway, where metformin binds to presenilin enhancer-2 (PEN2), making a complex that interacts with ATP6AP1 (V-ATPase subunit), inhibiting V-ATPase and activating AMPK (31,32). ...
... Although AMPK is directly activated as a consequence of ATP depletion, AMPK can be activated indirectly by the liver kinase B1 (LKB1), an upstream kinase that promotes AMPK activation through the phosphorylation of alpha (α) AMPK subunit, and through lysosomal pathway, where metformin binds to presenilin enhancer-2 (PEN2), making a complex that interacts with ATP6AP1 (V-ATPase subunit), inhibiting V-ATPase and activating AMPK (31,32). Consequently through AMPK activation, occurs: (I) the inhibition of mTOR, which mediates protein synthesis and cancer growth (33,34), (II) activation of p53, mediating cell cycle arrest, autophagy and apoptosis (35,36), (III) inactivation of acetyl-CoA carboxylase (ACC), reducing lipogenesis (37,38) and (IV) inhibition of adenylate cyclase (AC), histone deacetylase (HDAC) and CREB-regulated transcription coactivator 2 (CRTC2), which are involved with the reduction of gluconeogenesis genes transcription (22). Associated with the increase of NADH/NAD ratio, metformin reduces the tricarboxylic acid (TCA) cycle and its intermediates (39), which are used for cancer cells to energy production and macromolecule biosynthesis (40). ...
Background and objective:
Hematological malignancies (HMs) are a group of neoplasms with hematopoietic origin, currently divided into leukemias, lymphomas and multiple myeloma (MM). Although the advances in the management of HMs, the rate of drug resistance, relapse and refractory disease has been increasing, requiring new therapeutic strategies. In this review, we aim to summarize metformin's antitumoral mechanisms of action and present the latest studies of metformin action in HMs, including in resistant ones.
Methods:
For this review of literature, studies published between 1996 and 2023 from PubMed and clinical trials submitted to clinicaltrials.gov were considered.
Key content and findings:
Throughout this review we demonstrated the capacity of metformin to act as an anti-HMs drug, being able to re-sensitize HMs to classical anti-HMs agents and to overcome relapse and refractory HMs, as shown in vitro and in vivo studies. Associated with the potential anti-HM effect of metformin, some clinical trials are in progress, including in the view of reducing resistance and recurrence rate of HMs, which requires further exploration. The relationship among HMs cancer stem cells (HMs CSCs), drug resistance, cancer recurrence, and the effect of metformin in inhibiting CSCs were also discussed, despite this field needing more attention.
Conclusions:
In summary, metformin is a promising anti-HMs drug that can enhance patients' survival and prognosis through its action in the improvement of HMs response.
... Despite its clinical use for over 60 years, the precise mechanism of action of metformin remains incompletely understood. Recent research indicates that metformin disrupts glycolysis and oxidative phosphorylation [8][9][10], influencing Adenosine Triphosphate (ATP) production by activating AMP-activated protein kinase (AMPK) energy sensors [11][12][13]. The ATP production pathway is intricately connected to central carbon metabolism (CCM), encompassing traditional elements like glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid cycle (TCA). ...
... One of the hallmarks of cancer is the reprogramming of cellular energy metabolism, allowing tumor cells to sustain continuous growth and proliferation by substituting the metabolic program typically found in normal tissues. Drugs like 3 metformin, with the ability to exploit specific metabolic vulnerabilities in tumor cells, present a promising avenue for cancer treatment [23]. Indeed, lower incidences of certain types of cancer and/or improved overall survival has been reported in T2DM patients treated with metformin [22,24,25]. ...
Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin’s role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement of survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.
... Metformin has recently been repurposed or repositioned as a promising drug for cancer prevention and treatment (Andrzejewski et al., 2018;Tossetta, 2022) and as an anti-aging therapy (Mohammed et al., 2021). This trend appears to be consistent with the discovery of the molecular mechanisms of metformin. ...
... This trend appears to be consistent with the discovery of the molecular mechanisms of metformin. Metformin enters the cytoplasm through organic cation transporter member 1 (OCT1) (Wu et al., 2018) and directly acts on the mitochondria to decrease respiration instead of increasing aerobic glycolysis (Andrzejewski et al., 2018;Protti et al., 2012). This finding raises the possibility that platelet function and subsequent coagulation can be suppressed if a similar mechanism is observed in the platelets. ...
... It is generally thought that metformin incorporated into platelets (and other common cell types) inhibits complex I of the mitochondrial electron transport chain, thereby reducing ATP production in platelets (Andrzejewski et al., 2018;Siewiera et al., 2022). However, the mechanism by which metformin reduces and depletes intracellular ATP levels has not been elucidated. ...
Platelet-rich fibrin (PRF) is a popular autologous blood-derived biomaterial that is used in regenerative therapy. Owing to its simple preparation without additional factors, the PRF quality directly reflects the characteristics of individual blood samples. Antiplatelet or anticoagulant drugs can hamper the successful preparation of PRF. We recently observed similar phenomena in metformin-taking type-2 diabetics (T2DM). Thus, we hypothesized that metformin interferes with platelet function, thereby suppressing coagulation. For practical reasons, leukocyte- and platelet-rich plasma was prepared from healthy male donors (n = 9-15, age: 26-80 years) and treated with metformin (1-10 mM) for 24-72 h. Intrinsic and extrinsic coagulation activities were evaluated using prothrombin time (PT) and activated partial thromboplastin time (ATPP). Platelet adhesion and aggregation assays were performed using ADP stimulation. Among the parameters tested, APTT was the most sensitive and was significantly prolonged in the concentration range of 1-10 mM in a time- and concentration-dependent manner. Although obtained from healthy platelets and relatively higher concentrations of metformin, these findings suggest that metformin may induce further dysfunction of platelets to suppress intrinsic coagulation activity in T2DM patients, leading to failure of PRF preparation. This phenomenon may not have a severe impact on clinical diabetology or hematology. However, clinicians using PRF are recommended to be more sensitive to such information to avoid unexpected events in clinical settings.
... Decreased ATP levels led to the activation of AMP-activated protein kinase (AMPK), which activates the AMPK pathway and inhibits the mammalian target of rapamycin (mTOR), therefore enhancing tumor cell death [13]. Tumor cell death induced by metformin supports the expansion of tumor-infiltrating lymphocytes (TILs) [14,15]. Interestingly, metformin can also restore chemotherapy sensitivity by modulating NF-kB, ERK1/2 activation, autophagy, and the population of cancer stem cells [16]. ...
The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8+, CD4+ T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.
... To address this, 2DG-loaded PLGA nanoparticles (2DG-PLGA-NPs) were developed, which effectively promote tumor cell apoptosis, enhance IFN-g production in CD8 + T cells, and resist anti-PD-1 resistance when combined with sorafenib or anti-PD1 (153). Metformin, a typical diabetic drug, has potential antitumor properties by inhibiting glycolysis and glycogen synthesis (154). Metformin can reduce HK2 activity and impairs glycolysis, as well as indirectly inhibit HK2 by inhibiting IGF1-induced AKT phosphorylation (155). ...
Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the “Warburg effect,” sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of ‘education’ by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.
... While several studies reported the anticancer efficacy of the 2DG (glycolytic) inhibitor or metformin when used as a monotherapy in different cancer cells, including TNBCs, using a combination of 2DG and metformin was therapeutically more efficacious in inhibiting the growth of several cancer cells compared to monotherapy (using 2DG or metformin alone) [14,[19][20][21][22][23][24]. However, reports also suggest that differences in the metabolic profile of different cancers can influence how the various cancers respond to 2DG or metformin [31,37,38]. We hypothesized that the metabolic heterogeneity between the MDA-MB-231 and MDA-MB-468 cells could also thus alter their response to a combination of 2DG and metformin under 25 mM glucose conditions. ...
... 2B and 2 C). This can be explained by the fact that metformin reportedly inhibits the mitochondrial complex 1 and electron transport chain (ETC) [37,[42][43][44][45]. Metformin-mediated mitochondrial complex 1 inhibition causes an imbalance in the NAD/NADH and reduces oxygen consumption, thus reducing the energy (ATP) available to the cells for survival and proliferation [37,42]. ...
... 2B and 2 C). This can be explained by the fact that metformin reportedly inhibits the mitochondrial complex 1 and electron transport chain (ETC) [37,[42][43][44][45]. Metformin-mediated mitochondrial complex 1 inhibition causes an imbalance in the NAD/NADH and reduces oxygen consumption, thus reducing the energy (ATP) available to the cells for survival and proliferation [37,42]. In response to this metformin-mediated suppression of the tri-carboxylic acid (TCA) cycle, reduction in metabolite levels, and energy stress, the cells respond with a compensatory increase in glucose uptake and glycolytic flux while also switching to glutamine metabolism for survival and maintaining proliferation [37,42,46]. ...
Breast cancers (BCs) remain the leading cause of cancer-related deaths among women worldwide. Among the different types of BCs, treating the highly aggressive, invasive, and metastatic triple-negative BCs (TNBCs) that do not respond to hormonal/human epidermal growth factor receptor 2 (HER2) targeted interventions since they lack ER/PR/HER2 receptors remains challenging. While almost all BCs depend on glucose metabolism for their proliferation and survival, studies indicate that TNBCs are highly dependent on glucose metabolism compared to non-TNBC malignancies. Hence, limiting/inhibiting glucose metabolism in TNBCs should curb cell proliferation and tumor growth. Previous reports, including ours, have shown the efficacy of metformin, the most widely prescribed antidiabetic drug, in reducing cell proliferation and growth in MDA-MB-231 and MDA-MB-468 TNBC cells. In the current study, we investigated and compared the anticancer effects of either metformin (2 mM) in glucose-starved or 2-deoxyglucose (10 mM; glycolytic inhibitor; 2DG) exposed MDA-MB-231 and MDA-MB-468 TNBC cells. Assays for cell proliferation, rate of glycolysis, cell viability, and cell-cycle analysis were performed. The status of proteins of the mTOR pathway was assessed by Western blot analysis. Metformin treatment in glucose-starved and 2DG (10 mM) exposed TNBC cells inhibited the mTOR pathway compared to non-treated glucose-starved cells or 2DG/metformin alone treated controls. Cell proliferation is also significantly reduced under these combination treatment conditions. The results indicate that combining a glycolytic inhibitor and metformin could prove an efficient therapeutic approach for treating TNBCs, albeit the efficacy of the combination treatment may depend on metabolic heterogeneity across various subtypes of TNBCs.
... Therefore, metformin-mediated mitochondrial dysfunction and, as a consequence, energetic stress (low ATP/AMP) may promote a crucial cytotoxic condition for cancer cells; however, adaptation to the current rough metabolic situation is also probable. As a result, metformin may not always be cytotoxic to cancer cells, and those cells may continue to respond to metformin over the long term by replenishing ATP and metabolite levels [39]. Our research shows that when breast cancer and normal fibroblast cells are co-cultured, substantial phenotypic and secretory alterations may occur. ...
Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation, growth, and therapy resistance. The hallmarks of cancer-fibroblast interactions, consisting of caveolin 1 (Cav1) and mono-carboxylate transporter 4 (MCT4) (metabolic coupling markers), along with IL-6, TGFβ, and lactate secretion, are considered robust biomarkers predicting recurrence and metastasis. In order to promote a novel phenotype in normal fibroblasts, we predicted that breast cancer cells could be able to cause loss of Cav1 and increase of MCT4, as well as elevate IL-6 and TGFβ in nearby normal fibroblasts. We created a co-culture model using breast cancer (4T1) and normal fibroblast (NIH3T3) cell lines cultured under specific experimental conditions in order to directly test our theory. Moreover, we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cav1 and gain of MCT4 in adjacent fibroblasts and increase lactate secretion. These results were validated using the monoculture of each group separately as a control. In this system, we show that metformin inhibits IL-6 and TGFβ secretion and re-expresses Cav1 in both cells. However, MCT4 and lactate stayed high after treatment with metformin. In conclusion, our work shows that co-culture with breast cancer cells may cause significant alterations in the phenotype and secretion of normal fibroblasts. Metformin, however, may change this state and affect fibroblasts’ acquired phenotypes. Moreover, mitochondrial inhibition by metformin after 8 days of treatment, significantly hinders tumor growth in mouse model of breast cancer.
... Consequently, this increases the potential of metronomic approaches based on the oxidative phosphorylation (OXPHOS) inhibitors in the treatment of advanced (malignant) tumors. On the other hand, cellular adaptation to metabolic stress, for instance due to metabolic elasticity [24,25], may represent an important (although underestimated) factor that facilitates the survival of cancer cells in harmful microenvironments [26]. In particular, the switch from OXPHOS to aerobic glycolysis (Warburg effect) can help the cells to retain drug resistance in the presence of metabolic blockers. ...
... However, relatively mild cytostatic/pro-apoptotic responses of these cells to the combined DCX/MET-induced stress indicate that efficient drug-efflux systems limit the harmful effects of DCX on metabolic homeostasis. Additionally, the short-and longterm adaptation responses of these cells to bioenergetic challenges can be enhanced by their stress-induced microevolution toward metabolically elastic phenotype [24]. This notion is supported by the signs of Warburg effect observed in PC-3 WT populations during their long-term DCX-induced microevolution toward chemoresistant phenotype. ...
Background
Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed.
Methods
Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness.
Results
Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress.
Conclusions
Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.
... A combination of metformin and doxorubicin in the resistant MCF-7 and MDA-MB-231 cells presented more cytotoxicity than doxorubicin alone, while metformin acted via IFN-α signaling pathway and by induction of cellular oxidative stress [119]. Metformin causes energetic stress in cells by inhibiting complex I of the electron transport chain in mitochondria [120]. In addition, chemoresistant TNBC cells displayed an enhanced glycolytic phenotype with increased glucose uptake and lactate fermentation [83]. ...
Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and the highly invasive and proliferative nature of TNBC cells. Current treatments against TNBC have shown little promise due to high recurrence rate in patients. Consequently, there is a pressing need for novel and efficacious therapies against TNBC. Here, we report the discovery of a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. The anti-proliferative effects of this small molecule inhibitor were determined using 2D and 3D cell proliferation assays. We found that NSC33353 significantly reduces the proliferation of TNBC cells in these assays. Using proteomics, next generation sequencing (NGS), and gene enrichment analysis, we investigated global regulatory pathways affected by this compound in TNBC cells. Proteomics data indicate a significant metabolic reprograming affecting both glycolytic enzymes and energy generation through oxidative phosphorylation. Subsequently, using metabolic (Seahorse) and enzymatic assays, we validated our proteomics and NGS analysis findings. Finally, we showed the inhibitory and anti-tumor effects of this small molecule in vitro and confirmed its inhibitory activity in vivo. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug has been a major problem. We show that the combination of NSC33353 and doxorubicin suppresses the growth of TNBC cells synergistically, suggesting that NSC33353 enhances TNBC sensitivity to doxorubicin. In summary, our data indicate that the small molecule inhibitor, NSC33353, exhibits anti-tumor activity in TNBC cells, and works in a synergistic fashion with a well-known chemotherapeutic agent.
