Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions

Yu, Hongliang; Bian, Xiuhua; Gu, Dayong; He, Xia

doi:10.1155/2016/8678634

Cited by 19 publications

(16 citation statements)

References 22 publications

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“…Yu et al . showed that under glucose-deprivation conditions, metformin enhanced cisplatin cytotoxicity in an oesophageal SCC cell line, which could be comparable to our results 41 .…”

Section: Discussionsupporting

confidence: 92%

Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

Xie

et al. 2016

Sci Rep

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Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

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“…Yu et al . showed that under glucose-deprivation conditions, metformin enhanced cisplatin cytotoxicity in an oesophageal SCC cell line, which could be comparable to our results 41 .…”

Section: Discussionsupporting

confidence: 92%

Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

Xie

et al. 2016

Sci Rep

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“…Differences in the metformin concentration can result in a high glucose concentration in the medium. It has been reported that the concentration of glucose in solid tumor is ≤0.5 mmol/L, and cells cultured at low glucose concentrations have greater metformin sensitivity for cell viability than those cultured at high glucose concentrations . As a result, metformin may act specifically on solid tumor cells instead of on normal cells, and a high glucose concentration may mask the antitumor effects of metformin to some extent in vitro.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma

et al. 2018

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Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial‐mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti‐inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF‐κB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF‐κB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF‐κB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E‐cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E‐cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF‐κB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC.

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“…Pharmaceutical effect as well as chemosensitizing roles of metformin was dependent on culture conditions [ 30 – 32 ] and cell types [ 24 , 26 , 27 , 32 , 33 ]. Yu Hongliang et al found that metformin induced enhanced cytotoxicity of cisplatin only in glucose-deprivation medium [ 31 ]. We found that metformin at relatively high concentration synergizes with cisplatin via reversion of elevated intracellular glutathione induced by cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin

Zhao

Cheng

et al. 2017

Oncotarget

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Glutathione is the major intracellular anti-oxidant against reactive oxygen species and serves as a detoxification essential. The anti-diabetic drug metformin has been showed to exert anti-tumor activity via modulation of redox homeostasis. In this study, we provided evidence that metformin inhibits proliferation and induces apoptosis of esophageal squamous cancer cells. Importantly, we found that metformin acts as pro-oxidant via depletion of intracellular glutathione. Co-treatment with metformin reversed the elevated intracellular glutathione induced by cisplatin and therefore enhanced the sensitivity to cisplatin in vitro and in vivo. Taken together, our data indicate that combination of metformin with cisplatin may represent a novel therapeutic strategy for esophageal squamous cell carcinoma treatment.

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Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions

Cited by 19 publications

References 22 publications

Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma

Redox-dependent modulation of metformin contributes to enhanced sensitivity of esophageal squamous cell carcinoma to cisplatin

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