The anthelmintic flubendazole blocks human melanoma growth and metastasis and suppresses programmed cell death protein-1 and myeloid-derived suppressor cell accumulation.

Abstract

The incidence of melanoma is increasing faster than any other cancer. In recent years, treatment of melanoma and a range of other deadly cancers has involved immunotherapy with programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) checkpoint blockade which has improved survival. However, many patients do not respond or have partial response, survival benefit is in the order of months and all available PD-1/PD-L1 strategies are antibodies requiring intravenous infusion. There are no clinically approved small molecule pharmacologic inhibitors of the PD-1/PD-L1 system. The benzimidazole derivative flubendazole is a widely used anthelmintic available over the counter in Europe. Here we demonstrate the ability of flubendazole to inhibit human melanoma growth and spread in mice. Flubendazole's ability to block tumor growth and spread was comparable to paclitaxel. Anti-tumor effects were observed when flubendazole was delivered systemically not locally. Flubendazole inhibited CD31/PECAM-1 staining indicating suppression of tumor angiogenesis. Most surprisingly, flubendazole inhibited PD-1 levels within the tumors, but not PD-L1. Western blotting and flow cytometry revealed that flubendazole inhibits PD-1 expression in cultured melanoma cells. Flubendazole also reduced myeloid-derived suppressor cell (MDSC) levels in tumor tissue. Further we found that flubendazole inhibited active (phospho-Tyr705) signal transducer and activator of transcription (STAT3), an upstream regulator of PD-1 expression. These findings uncover that flubendazole is a novel small molecule inhibitor of not only melanoma growth and spread but also of PD-1 and MDSC.

• Authors: Yue Li, Grishma Acharya, Mina Elahy, Hong Xin, Levon M Khachigian
• Journal: Cancer letters (Cancer Lett) Vol. 459 Pg. 268-276 (09 10 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31128215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Antinematodal Agents
• Antineoplastic Agents
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• STAT3 Transcription Factor
• STAT3 protein, human
• Mebendazole
• flubendazole

Topics

• Animals
• Antinematodal Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Female
• Humans
• Lung Neoplasms (drug therapy, immunology, secondary)
• Mebendazole (analogs & derivatives, pharmacology)
• Melanoma (blood supply, drug therapy, pathology)
• Mice
• Mice, SCID
• Myeloid-Derived Suppressor Cells (drug effects, pathology)
• Neoplasm Metastasis
• Neovascularization, Pathologic (drug therapy)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Random Allocation
• STAT3 Transcription Factor (metabolism)
• Xenograft Model Antitumor Assays