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Metformin inhibited the viability of ESCC cells and normal esophageal epithelial cells. EC109 cells (a) and HEECs (b) were treated with metformin at different concentrations for 24 h (c), 48 h (d), and 72 h (e). Cell viability was evaluated by CCK-8. (f) IC50 of metformin in EC109 cells and HEECs at 24 h. IC50: half maximal inhibitory concentration. Data were presented as mean ± SD (n = 3). ∗P<0.05;∗∗P<0.01;∗∗∗P<0.001.
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The effect of metformin on human esophageal normal and carcinoma cells remains poorly understood. We aim to investigate the different antiproliferation effects and underlying distinct molecular mechanisms between these two types of cells. Human esophageal squamous cell carcinoma cell line, EC109, and normal esophageal epithelial cell line, HEEC, we...
Citations
... Additionally, MET induced apoptosis in esophageal carcinoma cells but not in normal esophageal epithelial cells, highlighting its differential effects on cancerous versus normal cells. 14 Various studies showed that the MET is not only capable of decreasing the risk of cancer in patients suffering from diabetes but could also prevent and treat nondiabetic patients suffering from pancreatic, bladder, lung, breast, thyroid, and prostate cancers. [15][16][17][18] Besides, MET showed promising results in averting colorectal cancer, squamous cell carcinoma, oral ductal carcinoma in situ, human cholangiocarcinoma, and endometrial cancer. ...
Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5′ AMPK, thereby inhibiting he development and progression of Cell Biochem Funct. 2024;42:e4071. wileyonlinelibrary.com/journal/cbf various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its
... Numerous studies have delved into the in vitro and in vivo consequences of metformin on ESCC and EAC cells, with predominant emphasis on two pathways: the signal transducer and activator of transcription 3 (Stat3)/Bcl-2 pathway [54][55][56] and the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway [57]. Additionally, more recent studies have explored the anti-tumor activity of metformin through the modulation of redox homeostasis [58][59][60]. ...
... The pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, metformin treatment led to the inactivation of Stat3 and its downstream target Bcl-2 [54][55][56]. Consequently, small interfering RNA (siRNA)-mediated Stat3 knockdown heightened metformin-induced autophagy and apoptosis, concurrently intensifying the inhibitory impact of metformin on cell viability. Similarly, metformin repressed the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy. ...
... In Vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and hindered tumor growth. In summary, the deactivation of the Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy [54,55]. To further corroborate the aforementioned findings, Shaffee et al., by concentering primarily on ESCC TE8 and TE11 cells, substantiated the conclusion that metformin induces apoptosis in ESCC by suppressing Bcl-2 expression and elevating p53 levels [56]. ...
Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin’s influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin’s potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin’s candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin’s role in EC management, potentially improving patient care and outcomes.
... The human ESCC cell lines EC109 and EC9706 were gifts from Dr. Jing Yu and Dr. Xianbin (Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, China) (Peng et al., 2020;Yu et al., 2019). Cells were maintained in RPMI-1640 medium (HIMEDIA, Mumbai, India) with 10% fetal bovine serum (FBS; HyClone, Logan, UT, United States) in an atmosphere of 5% CO 2 at 37°C. ...
Cadmium (Cd) exposure has been implicated in the etiology of esophageal squamous cell carcinoma (ESCC), albeit with inconsistent results from epidemiologic studies and without causal evidence. In this study, we explore the relationship of Cd exposure and the development, progression and therapeutic resistance of ESCC. A total of 150 ESCC patients and 177 matched controls from a coastal region with a high incidence of ESCC in China were included in the study. It was found that the median blood Cd level (BCL) was significantly higher in ESCC patients than that in the controls. Odds ratios for ESCC risk were 3.12 (95% CI 1.54-6.30) and 3.71 (95% CI 1.84-7.48) in the third and fourth quartiles of Cd distribution, respectively. Notably, BCL above 4.71 μg/L was strongly associated with shorter progression-free survival time compared to that below 1.60 μg/L ( p < 0.001). The chronic Cd-treated ESCC cells (CCT-ESCC) CCT-EC109 and CCT-EC9706 exhibited increased cell proliferation and tumorigenesis, enhanced migration and invasion, and upregulated EMT biomarkers following 12 weeks of exposure to 5 μM cadmium chloride. Furthermore, Cd treatment attenuated the efficacy of 5-fluorouracil, cisplatin and irradiation treatment in CCT-ESCC cells both in vitro and in vivo . Moreover, we revealed that Cd stimulated the cancer cell stemness and Wnt/β-catenin signaling pathway in the CCT-ESCC cells. Additionally, 5-aza-2-deoxy-cytidine treatment resulted in suppression of the Wnt/β-catenin signaling pathway and rescue of the Cd-induced cell radioresistance. These results offer new insights into the role of environmental Cd exposure in the development, progression and chemoradioresistance of ESCC.
Signal transducers and activators of transcription 3 (STAT3) signaling plays an important role in mediating tumor progression, inflammation, cardiovascular disease, and other pathological processes.In recent years, STAT3 as a therapeutic target has received extensive attention. It is well known that metformin can play the role of hypoglycemia by activating AMP-activated protein kinase (AMPK) through inhibition of mitochondrial ATP production.However, AMPK is not required for metformin activity.Although the application of STAT3 as a therapeutic target of metformin is still in the initial research stage, the importance of STAT3 in the mechanism of metformin is gradually being recognizedand further studies are needed to demonstrate the important role of the STAT3 regulatory network in the regulation of diseases by metformin. Here, we reviewed in detail that metformin inhibits the progression of various diseases like tumors, autoimmune diseases and hormone-related diseases by regulating multiple signaling pathways such as JAK/STAT3 and mTOR/STAT3 signaling centered on STAT3. We also summarized recent advances of STAT3 inhibitors combined with metformin in the treatment of diseases.We emphasized that STAT3 signaling, as an AMPK-independent signaling pathway, may be an important target for metformin in clinical therapy.
Polycyclic aromatic systems have been considered good biological probes, but some may also be good scaffolds for drug development. In this study, a series of benzobis(imidazole) derivatives were identified as STAT3 signal inhibitors, among which compound 24 showed significant inhibition of IL-6 induced JAK/STAT3 signalling pathway activation. Moreover, 24 inhibited cancer cell growth and migration, and induced cell apoptosis as well as cycle arrest in human hepatocellular carcinoma cells (HepG2) and oesophageal carcinoma cells (EC109). Compound 24 also displayed obvious antitumor activity in a mouse HepG2 cell xenograft tumor model without affecting the body weight. These results confirmed that 24 was a potential STAT3 signal inhibitor with certain antitumor activity.
