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Metformin sensitizes hypoxia-induced gefitinib treatment resistance of HNSCC via cell cycle regulation and EMT reversal

Authors Yin XT, Wei Z, Song CH, Tang CC, Xu WG, Wang YF, Xie JQ, Lin ZT, Han W

Received 17 June 2018

Accepted for publication 20 August 2018

Published 19 November 2018 Volume 2018:10 Pages 5785—5798

DOI https://doi.org/10.2147/CMAR.S177473

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 4

Editor who approved publication: Dr Beicheng Sun


Xiteng Yin,1,2,* Zheng Wei,1,2,* Chuanhui Song,1,2 Chuanchao Tang,1,2 Wenguang Xu,1,2 Yufeng Wang,1,2 Junqi Xie,1,2 Zitong Lin,2,3 Wei Han1,2

1Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China; 2Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China; 3Department of Dentomaxillofacial Radiology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China

*These authors contributed equally to this work

Objectives: The objectives of this study were to explore the mechanisms of metformin sensitization to hypoxia-induced gefitinib treatment in resistant head and neck squamous cell carcinoma (HNSCC) and evaluate the effects of this combined treatment strategy.
Methods: The effects of gefitinib treatment on HNSCC were measured under normoxic and hypoxic conditions. The relationship between hypoxia and cell cycle and epithelial–mesenchymal transition (EMT) in tumor cells were analyzed. Palbociclib and LY294002 were used in combination with gefitinib to evaluate the effects on HNSCC cell cytotoxicity during hypoxia. Finally, metformin was used to evaluate the sensitizing effects of gefitinib treatment on HNSCC in vivo and in vitro.
Results: Cell viability and apoptosis assays demonstrated a significant difference in HNSCC cells treated with gefitinib between the normoxia and hypoxia groups. Hypoxia induced the expression of cyclin D1, decreased the percentage of cells in G1, and promoted the EMT of tumor cells. Both palbociclib and LY294002 enhanced gefitinib-induced cytotoxicity of HNSCC cells under hypoxic conditions. Encouragingly, metformin sensitized HNSCC to gefitinib treatment in vivo and in vitro.
Conclusion: Hypoxia promotes G1–S cell cycle progression and EMT in HNSCC, resulting in gefitinib treatment resistance. Metformin sensitizes HNSCC to gefitinib treatment, which might serve as a novel combined treatment strategy.

Keywords: tumor hypoxia, gefitinib resistance, metformin

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