Repurposing metabolic regulators: antidiabetic drugs as anticancer agents

Molecular Biomedicine, Год журнала: 2024, Номер 5(1)

Опубликована: Сен. 28, 2024

Abstract Drug repurposing in cancer taps into the capabilities of existing drugs, initially designed for other ailments, as potential treatments. It offers several advantages over traditional drug discovery, including reduced costs, development timelines, and a lower risk adverse effects. However, not all classes align seamlessly with patient's condition or long-term usage. Hence, chronically used drugs presents more attractive option. On hand, metabolic reprogramming being an important hallmark paves regulators possible therapeutics. This review emphasizes importance current insights antidiabetic metformin, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) glucagon-like peptide-1 receptor agonists (GLP-1RAs), thiazolidinediones (TZD), α-glucosidase against various types cancers. Antidiabetic regulating pathways have gained considerable attention research. The literature reveals complex relationship between risk. Among metformin may possess anti-cancer properties, potentially reducing cell proliferation, inducing apoptosis, enhancing sensitivity to chemotherapy. revealed heterogeneous responses. Sulfonylureas TZDs demonstrated consistent activity, while SGLT2 inhibitors DPP-4 shown some benefits. GLP-1RAs raised concerns due associations increased certain highlights that further research is warranted elucidate mechanisms underlying effects these establish their efficacy safety clinical settings.

Язык: Английский

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Dietary Restrictions and Cancer Prevention: State of the Art

Nutrients, Год журнала: 2025, Номер 17(3), С. 503 - 503

Опубликована: Янв. 29, 2025

Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise 16.3 by 2040. Primary prevention has long been acknowledged as crucial approach reducing incidence. In fact, between 30 and 50 percent of all tumors are known be preventable eating healthy diet, staying active, avoiding alcohol, smoking, being overweight. Accordingly, many international organizations have created tumor guidelines, which underlie the importance following diet emphasizes plant-based foods while minimizing consumption red/processed meat, sugars, processed foods, alcohol. However, further research needed define relationship effect specific diets or nutritional components on prevention. Interestingly, reductions food intake dietetic restrictions can extend lifespan yeast, nematodes, flies, rodents. Despite controversial results humans, those approaches potential ameliorate health via direct indirect effects signaling pathways involved onset. Here, we describe latest knowledge cancer-preventive dietary biochemical processes involved. Molecular, preclinical, clinical studies evaluating different fasting strategies will also reviewed.

Язык: Английский

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Metformin exerted tumoricidal effects on colon cancer tumoroids via the regulation of autophagy pathway

Stem Cell Research & Therapy, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 4, 2025

Despite the existence of promising outcomes from standard 2D culture systems, these data are not completely akin to in vivo tumor parenchyma. Therefore, development and fabrication various 3D systems can part mimic intricate cell-to-cell interaction within real mass. Here, we aimed evaluate tumoricidal impacts metformin (MTF) on colorectal cancer (CRC) tumoroids an vitro system via modulation autophagy. CRC were developed using human umbilical vein endothelial cells (HUVECs), adenocarcinoma HT29 cells, fibroblasts (HFFF2) a ratio 1: 2: 1 2.5% methylcellulose. Tumoroids exposed different concentrations MTF, ranging 20 1000 mM, for 72 h. The survival rate was detected LDH release assay. expression protein levels autophagy-related factors measured PCR array western blotting, respectively. Using H & E, immunofluorescence staining (Ki-67), integrity proliferation examined. current protocol yielded typical compact with dark central region. slight changes released contents, no statistically significant differences achieved terms cell toxicity MTF-exposed groups compared control tumoroids, indicating insufficiency MTF induction death (p > 0.05). Western blotting indicated that LC3II/I reduced 120 mM < These coincided reduction intracellular p62 content mM-treated 40 analysis confirmed up-regulation, down-regulation several genes related signaling transduction pathways associated autophagy machinery shared effectors between apoptosis non-treated group more prominent incubated MTF. Histological examination loosening MTF-treated groups, especially increase (chromatin marginalization) necrotic (pyknotic nuclei) changes. In group, spindle-shaped remnants fibrillar matrix detected. Data proliferating Ki-67+ by increasing concentration mM. Different autophagy/apoptosis modulated after treatment coinciding both apoptotic tumoroid structure. inhibit dose-dependent manner.

Язык: Английский

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Cellular and Molecular Evidence of the Synergistic Antitumour Effects of Hydroxytyrosol and Metformin in Prostate Cancer

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1341 - 1341

Опубликована: Фев. 5, 2025

Prostate cancer (PCa) is the tumour pathology with second highest incidence among men worldwide. PCa strongly influenced by obesity (OB), which increases its aggressiveness. Hence, some metabolic drugs like metformin have emerged as potential anti-tumour agents against several endocrine-related cancers. Likewise, a high adherence to Mediterranean diet has been associated lower rates of OB and reduction in aggressiveness since this contains phenolic bioactive compounds such hydroxytyrosol (HT) that mainly present extra virgin olive oil. Thus, we decided analyse therapeutic combination HT + different cell models. Specifically, combinations doses were evaluated analysing proliferation rate LNCaP, 22Rv1, DU-145, PC−3 cells using SynergicFinder method. The results revealed synergistic effect significantly reducing proliferation, especially LNCaP cells. This was also confirmed migration tumoursphere formation assays LNCaP. effects on cycle apoptosis assessed flow-cytometry, arrest G1 phase an increase late observed metformin. phosphorylation levels critical components oncogenic pathways measured reduced activity multiple MAPK, AKT, TGF-β pathways. Overall, might represent new avenue for management patients, observation certainly warrants further investigation through well-designed clinical trial.

Язык: Английский

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Synergistic anti-cancer effects of metformin and cisplatin on YD-9 oral squamous carcinoma cells via AMPK pathway

Journal of Applied Oral Science, Год журнала: 2025, Номер 33

Опубликована: Янв. 1, 2025

Abstract Objective This study evaluated whether hypoglycemic drug metformin enhances the anti-cancer effects of cisplatin in YD-9 cells. Methodology cells, derived from oral mucosal squamous cell carcinoma mucosa, were used to assess combined and by means MTT assay, live dead staining, colony formation assays evaluate viability proliferation. Reactive oxygen species level was measured using a Muse analyzer. Apoptosis, epithelial-mesenchymal transition, related molecular pathways analyzed western blot. Wound healing Transwell migration examined migration, whereas monophosphate-activated protein kinase inhibitor Compound C, utilized investigate AMPK pathway. Results Sequential treatment cells with resulted decreased proliferation, increased ROS levels, elevated apoptosis compared individual drugs. Moreover, inhibited EMT, wound healing, migration. These results correlated phosphorylation, key regulator cellular energy homeostasis. Introduction C pre-treatment upregulated N-cadherin α-smooth muscle actin along enhanced Conclusion found synergism between cisplatin. Additionally, introduction confirmed that EMT inhibition is dependent. findings indicate potential use as an adjunct treatments, warranting further investigation.

Язык: Английский

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Anti-Diabetic Therapies and Cancer: From Bench to Bedside

Biomolecules, Год журнала: 2024, Номер 14(11), С. 1479 - 1479

Опубликована: Ноя. 20, 2024

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention its potential anti-cancer effects, primarily through modulation AMP-activated protein kinase/mammalian target rapamycin (AMPK/mTOR) pathway and induction autophagy. Beyond metformin, other conventional treatments, such as insulin, sulfonylureas (SUs), pioglitazone, dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined their roles in biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) sodium-glucose co-transporter-2 (SGLT-2) revolutionized DM management by not only improving glycemic control but delivering substantial cardiovascular renal benefits. Given diverse metabolic including anti-obesogenic properties, agents now under meticulous investigation influence tumorigenesis advancement. This review aims to offer comprehensive exploration evolving landscape glucose-lowering treatments implications biology. It critically evaluates experimental evidence surrounding molecular mechanisms which medications may modulate oncogenic signaling pathways reshape tumor microenvironment (TME). Furthermore, it assesses translational research clinical trials gauge practical relevance real-world settings. Finally, explores adjuncts treatment, particularly enhancing efficacy chemotherapy, minimizing toxicity, addressing resistance within framework immunotherapy.

Язык: Английский

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Unlocking new potential: the evolving landscape of metformin repurposing trials

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 7, 2025

Язык: Английский

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Mitochondrial metabolism-related features guiding precision subtyping and prognosis in breast cancer, revealing FADS2 as a novel therapeutic target

Translational Oncology, Год журнала: 2025, Номер 54, С. 102330 - 102330

Опубликована: Фев. 21, 2025

Язык: Английский

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Metformin-induced E6/E7 inhibition prevents HPV-positive cancer progression through p53 reactivation

Anti-Cancer Drugs, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

The human papillomavirus (HPV) is implicated in multiple lethal cancers, although it more sensitive to certain therapies than HPV-negative cancers. Therefore, the development of targeted therapeutic strategies imperative. HPV oncogenes E6/E7 are ideal targets for HPV-positive cancer, but there no clinical that have been proven effectively target E6/E7. Notably, metformin significantly inhibits expression; however, underlying mechanism and potential remain unclear, limiting its translation. Cell Counting Kit-8, ethynyl-2′-deoxyuridine, terminal-deoxynucleotidyl transferase-mediated Nick end labeling assays were conducted evaluate effects on cell viability, proliferation, apoptosis. Quantitative real-time PCR, western blotting, immunofluorescence performed determine changes p53 expression levels following treatment. Patient-derived organoids in-vivo xenograft models constructed anticancer activity against cancer. Our research demonstrated enhanced sensitivity cancer cells metformin. Mechanistic studies revealed exerts by inhibiting expression, which associated with reactivation. Furthermore, we substantiated patient-derived tumor models. study focused responsiveness metformin, highlighting as a strategy

Язык: Английский

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The Influence of Performance Status, Inflammation, and Nutrition on the Impact of SGLT2 Inhibitors on Cancer Outcomes

Cancer Medicine, Год журнала: 2025, Номер 14(6)

Опубликована: Март 1, 2025

Sodium-glucose-linked transporter 2 inhibitors (SGLT2i) may have antitumor effects. Previous studies analyzing their role in mortality and progression did not account for potential confounders, including cancer treatment, performance status, inflammatory markers, nutritional status. This study aims to evaluate the impact of SGLT2i treatment on while considering these confounders. A retrospective cohort was conducted. total 526 patients with (302 women, mean age 64 years, range 40-79 years) were divided into two cohorts based whether they taking at time diagnosis followed 1 year or until death. All drugs standard clinical doses. Additional data collected included basic demographic variables, metabolic lifestyle characteristics, received, The primary endpoints progression. Patients (n = 41) more likely type diabetes, be male, ever-smokers, older than SGLT2i. In univariate analyses, associated Instead, positively a T2D, male sex, age, heavy alcohol drinking, ever-smoker poor increased inflammation, malnutrition, tumor site, stage, lack treatment. After adjusting significantly Our results suggest that outcomes is limited under dosing conditions.

Язык: Английский

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