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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer by incidence worldwide with an annual incidence of approximately 600,000 cases [1,2,3]
We first compared the anti-proliferative effect of mebendazole (MBZ) with that of the clinically used chemotherapeutic agent cisplatin (CIS) in two commonlyused human HNSCC lines CAL27 and SCC15
When these lines were treated with cisplatin, a dose-dependent inhibition of cell proliferation was observed (Figure 1A) and a significant inhibitory effect was seen at 20 μM and 40 μM for CAL27 and SCC15 cells, respectively, CAL27 cells were more sensitive to cisplatin than SCC15 cells (Figure 1A ab vs. cd)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer by incidence worldwide with an annual incidence of approximately 600,000 cases [1,2,3]. It is urgent to improve the five-year survival rate of HNSCC patients. Cisplatin is used as one of the first-tier chemotherapeutic drugs against human HNSCC its therapeutic effect has been less than satisfactory [5]. HNSCC patients receiving chemotherapy still proceed to the advanced stage, cancer local recurrence, or metastasizing to regional lymph nodes and/or distant organs largely due to the development of resistance to cisplatin and/or other agents [6, 7]. There is an urgent clinical need to develop novel and effective anticancer agents for efficacious HNSCC treatment
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