Abstract
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.
Highlights
Characteristic feature of the tumour microenvironment is inflammation, which contributes to carcinogenesis, cancer invasion, and metastasis[17]
We proved that metformin could sensitize the response of oral squamous cell carcinoma (OSCC) to cisplatin treatment through inhibition of NF-κB/hypoxia-inducible factors (HIFs)-1αsignaling both in vitro and in vivo, which might serve as a novel chemo-regimen for tumour microenvironment-targeted therapy
The results showed that the 50% inhibitory concentration (IC50) values of HSC3, SCC3, and TCA8113 cells exposed to hypoxia were significantly higher than those exposed to normoxia following a 48-h cisplatin treatment (Fig. 1A and Table 1)
Summary
Characteristic feature of the tumour microenvironment is inflammation, which contributes to carcinogenesis, cancer invasion, and metastasis[17]. We proved that NF-κB was located upstream of the HIF-1αpromoter[19], with the function of regulating HIF-1αtranscription, which was fairly consistent with some of the previous studies[18,20,21]. The crucial role of HIF-1αin chemoresistance indicates that an effective approach could be provided to overcome chemoresistance through the inhibition of the upstream key factor—NF-κB. Encouraging outcomes from a few clinical studies have shown that metformin may contribute to a better treatment response among cancer patients[25,26]. We proved that metformin could sensitize the response of OSCC to cisplatin treatment through inhibition of NF-κB/HIF-1αsignaling both in vitro and in vivo, which might serve as a novel chemo-regimen for tumour microenvironment-targeted therapy
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