Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

Abstract

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

• Authors: Sakibul Huq, Joshua Casaos, Riccardo Serra, Michael Peters, Yuanxuan Xia, Andy S Ding, Jeff Ehresman, Jayanidhi N Kedda, Manuel Morales, Noah L Gorelick, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 9 Pg. 1797-1808 (09 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32606016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• EIF4E protein, human
• Eukaryotic Initiation Factor-4E
• Radiation-Sensitizing Agents
• SNAI1 protein, human
• Snail Family Transcription Factors
• Ribavirin
• IMP Dehydrogenase
• IMPDH1 protein, human
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Animals
• Cell Cycle Checkpoints (drug effects, radiation effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• Cell Survival (drug effects, radiation effects)
• Chemoradiotherapy
• Drug Repositioning
• Enhancer of Zeste Homolog 2 Protein (metabolism)
• Eukaryotic Initiation Factor-4E (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• IMP Dehydrogenase (metabolism)
• Mice
• Molecular Targeted Therapy
• Nasopharyngeal Carcinoma (metabolism, therapy)
• Nasopharyngeal Neoplasms (metabolism, therapy)
• Radiation-Sensitizing Agents (administration & dosage, pharmacology)
• Ribavirin (administration & dosage, pharmacology)
• Snail Family Transcription Factors (metabolism)
• Xenograft Model Antitumor Assays