Tsou Yung-An, Chang Wei-Chao, Lin Chia-Der, Chang Ro-Lin, Tsai Ming-Hsui, Shih Liang-Chun, Staniczek Theresa, Wu Tsu-Fang, Hsu Hui-Ying, Chang Wen-Dien, Lai Chih-Ho, Chen Chuan-Mu
Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 406, Taiwan.
Department of Life Sciences, and Ph.D. program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan.
Pharmaceuticals (Basel). 2021 Feb 26;14(3):191. doi: 10.3390/ph14030191.
Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer.
下咽鳞状细胞癌（HSCC）通常在晚期才被诊断出来，导致预后较差。即使在手术技术、化疗和放疗技术有所改进之后，HSCC的生存率仍然很低。二甲双胍常用于治疗2型糖尿病（DM），有人认为它可以降低患各种癌症的风险。然而，只有少数临床研究提到了二甲双胍的使用与HSCC之间的关系。因此，本研究的目的是阐明二甲双胍在下咽癌中的具体作用及作用机制。我们首先通过开展一项回顾性队列研究，评估二甲双胍的使用对患有DM的下咽癌患者是否有影响。我们的结果显示，使用二甲双胍的DM下咽癌患者的总生存率显著高于未接受二甲双胍治疗的患者。基于细胞的分析进一步表明，二甲双胍治疗可调节p38/JNK信号通路，以降低细胞周期蛋白D1和Bcl-2的表达。此外，二甲双胍激活了AMPKα和MEK/ERK信号通路，使细胞中的p27（Thr198）磷酸化，并降低mTOR的磷酸化水平。这些作用促使细胞进入G1期细胞周期停滞、凋亡和自噬状态。我们的研究结果通过结合临床队列分析和体外研究表明，二甲双胍可用于重新定位药物，以治疗患有下咽癌的DM患者。
