Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis

Abstract

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.

Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe3O4 Nanoparticles

“…Cultured cells or homogenized liver tissues were trypsinized and fixed with fixing solution (1% FBS and 4% formaldehyde in PBS) for 10 min at 37 °C, permeabilized with 100% methanol for 30 min on ice, and blocked with 4% BSA in PBS for 1 h at room temperature. Then, human FVIII antibody (1:250 dilutions; Abcam, Cambridge, UK) was added overnight for incubation at 4 °C, and Alexa Fluor ® 546 dye-conjugated secondary antibody (1:500) was added at room temperature for 1 h. Samples were filtered and analyzed by flow cytometry (Accuri ® C6 Plus; BD Biosciences, Franklin Lakes, NJ, USA) [ 41 ].…”

Metformin Intervention—A Panacea for Cancer Treatment?

“…There is growing interest in the potential benefits of metformin in cancer treatment and prevention [ 60 ]. Tumorigenesis is a complex relationship of metabolic processes that requires a number of steps, in which hyperglycemia may be the main modulator.…”

“…In many studies performed in a group of lung cancer patients treated with metformin, decreased proliferation of cancer cells and increased apoptosis were reported [ 102 , 131 , 132 , 133 , 134 ]. Growing evidence from epidemiological and observational studies shows that metformin may be an effective adjuvant anti-cancer therapy [ 24 , 60 , 132 ].…”

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

“…In HNSCC, one of the known action mechanisms of metformin is through inactivation of mTOR signaling, as shown in Figure 1. In hypopharyngeal cancer cells, p-mTOR was reduced through activation of ERK and AMPK signaling pathways by metformin, resulting in cell cycle arrest, apoptosis and autophagy triggering [113]. In oral squamous cell carcinomas (OSCC), metformin decreased expression of YES1-associated transcriptional regulator (YAP), an effector of the Hippo signaling pathway, and YAP overexpression reduced metformin inhibition on mTOR and c-MYC expression [114].…”