STAT3 as a therapeutic target in the metformin-related treatment

Zhang, Weiran; Li, Daisong; Li, Bing; Chu, Xiangcheng; Kong, Bin

doi:10.1016/j.intimp.2023.109770

Cited by 14 publications

(4 citation statements)

References 121 publications

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“…Effects of metformin on the immune compartment have been elucidated primarily in the context of tumor therapy. Here, metformin was shown to exert anti-tumor effects on several levels, including the reprogramming of cells within the tumor microenvironment via activation of AMPK and by inhibition of STAT3 [429] and NF-κB [430]. In agreement, metformin inhibited the SASP phenotype of senescent cells by preventing nuclear translocation of NF-κB and activating NF-κB inhibitor α in an AMPK-independent manner [431].…”

Section: Metforminmentioning

confidence: 87%

Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?

2023

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Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells under basal conditions, termed inflammaging, contributes to impaired innate immune responsiveness towards pathogen-mediated stimulation and limits antigen-presenting activity. Adaptive immune responses are attenuated as well due to lowered numbers of naïve lymphocytes and their impaired responsiveness towards antigen-specific stimulation. Additionally, the numbers of immunoregulatory cell types, comprising regulatory T cells and myeloid-derived suppressor cells, that inhibit the activity of innate and adaptive immune cells are elevated. This review aims to summarize our knowledge on the cellular and molecular causes of immunosenescence while also taking into account senescence effects that constitute immune evasion mechanisms in the case of chronic viral infections and cancer. For tumor therapy numerous nanoformulated drugs have been developed to overcome poor solubility of compounds and to enable cell-directed delivery in order to restore immune functions, e.g., by addressing dysregulated signaling pathways. Further, nanovaccines which efficiently address antigen-presenting cells to mount sustained anti-tumor immune responses have been clinically evaluated. Further, senolytics that selectively deplete senescent cells are being tested in a number of clinical trials. Here we discuss the potential use of such drugs to improve anti-aging therapy.

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Section: Metforminmentioning

confidence: 87%

Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?

2023

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“…Metformin has shown the ability to block HER2 tyrosine kinase activity [ 24 ], and breast cancer cells with overexpression of HER2 have improved metformin-induced inhibition of cell growth [ 25 ]. Finally, studies also suggest that metformin can inhibit several STAT3-related signaling pathways known to be involved in breast cancer, including IL-6/JAK2/STAT3 signaling [ 26 ]. In addition, at least in triple-negative breast cancer cells in vitro, metformin can reduce the activation (phosphorylation) of STAT3 but does not alter STAT3 expression levels.…”

Section: Preclinical Evidence: Findings From In Vitro and In Vivo Modelsmentioning

confidence: 99%

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

Corleto,

Strandmo,

Giles

2024

Pharmaceuticals

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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.

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“…Signal transducer and activator of transcription (STAT) is a unique family of proteins that can bind to DNA 316 . The STAT family consists of STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6 317,318 . STAT proteins, particularly STAT3 and 5 transduce signals from cytokines and growth factors through their receptors to the nucleus to regulate expression of a variety of genes, leading to cell proliferation, apoptosis inhibition, and chemo‐resistance 319,320 (PMID: 36596870).…”

Section: Crbn Ligands and Their Utilizations In Protacsmentioning

confidence: 99%

“… 316 The STAT family consists of STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. 317 , 318 STAT proteins, particularly STAT3 and 5 transduce signals from cytokines and growth factors through their receptors to the nucleus to regulate expression of a variety of genes, leading to cell proliferation, apoptosis inhibition, and chemo‐resistance 319 , 320 (PMID: 36596870). As promising classical targets for the treatment of human cancers, several small molecule inhibitors targeting STAT3 and STAT5 have entered clinical trials, but none of them have been in clinical use.…”

Section: Crbn Ligands and Their Utilizations In Protacsmentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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STAT3 as a therapeutic target in the metformin-related treatment

Cited by 14 publications

References 121 publications

Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?

Counteracting Immunosenescence—Which Therapeutic Strategies Are Promising?

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

PROTACs: A novel strategy for cancer drug discovery and development

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