Anthelmintic mebendazole enhances cisplatin’s effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC)

// Fugui Zhang 1, 2 , Yong Li 1 , Hongmei Zhang 1, 2 , Enyi Huang 1, 2 , Lina Gao 1 , Wenping Luo 1, 2 , Qiang Wei 2, 3 , Jiaming Fan 2, 3 , Dongzhe Song 2, 4 , Junyi Liao 2, 3 , Yulong Zou 2, 3 , Feng Liu 2, 3 , Jianxiang Liu 2, 5 , Jiayi Huang 2, 3 , Dan Guo 2, 3 , Chao Ma 2, 6 , Xue Hu 2, 3 , Li Li 2, 7 , Xiangyang Qu 2, 3 , Liqun Chen 2, 3 , Xinyi Yu 2, 3 , Zhicai Zhang 2, 5 , Tingting Wu 2, 8 , Hue H. Luu 2 , Rex C. Haydon 2 , Jinlin Song 1 , Tong-Chuan He 1, 2, 3 , Ping Ji 1 1 Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, and the Affiliated Hospital of Stomatology of Chongqing Medical University, Chongqing, China 2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA 3 Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China 4 Department of Conservative Dentistry and Endodontics, West China Hospital and West China School of Stomatology, Sichuan University, Chengdu, China 5 Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 6 Department of General Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China 7 Department of Biomedical Engineering, School of Bioengineering, Chongqing University, Chongqing, China 8 Department of Neurosurgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China Correspondence to: Tong-Chuan He, email: tche@uchicago.edu Ping Ji, email: jiping-62@hotmail.com Keywords: head and neck squamous cell carcinoma, mebendazole, drug repurposing, keratinization, differentiation therapy Received: October 17, 2016      Accepted: January 09, 2017      Published: January 16, 2017 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.