title: Anthelmintic mebendazole enhances cisplatin's effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC).
abstract: Head and neck squamous cell carcinoma (HNSCC) is one of the most common and aggressive types of human cancers worldwide. Nearly a half of HNSCC patients experience recurrence within five years of treatment and develop resistance to chemotherapy. Thus, there is an urgent clinical need to develop safe and novel anticancer therapies for HNSCC. Here, we investigate the possibility of repurposing the anthelmintic drug mebendazole (MBZ) as an anti-HNSCC agent. Using the two commonly-used human HNSCC lines CAL27 and SCC15, we demonstrate MBZ exerts more potent anti-proliferation activity than cisplatin in human HNSCC cells. MBZ effectively inhibits cell proliferation, cell cycle progression and cell migration, and induces apoptosis of HNSCC cells. Mechanistically, MBZ can modulate the cancer-associated pathways including ELK1/SRF, AP1, STAT1/2, MYC/MAX, although the regulatory outcomes are context-dependent. MBZ also synergizes with cisplatin in suppressing cell proliferation and inducing apoptosis of human HNSCC cells. Furthermore, MBZ is shown to promote the terminal differentiation of CAL27 cells and keratinization of CAL27-derived xenograft tumors. Our results are the first to demonstrate that MBZ may exert its anticancer activity by inhibiting proliferation while promoting differentiation of certain HNSCC cancer cells. It's conceivable the anthelmintic drug MBZ can be repurposed as a safe and effective agent used in combination with other frontline chemotherapy drugs such as cisplatin in HNSCC treatment.
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.|Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Fugui
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.|Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.|Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Enyi
authors.initials: E
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Gao
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.|Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Wenping
authors.initials: W
authors.lastname: Luo
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Fan
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of Conservative Dentistry and Endodontics, West China Hospital and West China School of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Dongzhe
authors.initials: D
authors.lastname: Song
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Liao
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Guo
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of General Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Hu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of Biomedical Engineering, School of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Qu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Yu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Department of Neurosurgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.affiliation: Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Song
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.|Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.|Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.affiliation: Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D008297:Male; D008463:Mebendazole / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000969:Antinematodal Agents; D000970:Antineoplastic Agents; D008463:Mebendazole; D002945:Cisplatin
keywords: differentiation therapy; drug repurposing; head and neck squamous cell carcinoma; keratinization; mebendazole