A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma
Abstract
Monocarboxylate transporters (MCTs) support tumour growth by regulating the transport of metabolites in the tumour microenvironment. High MCT1 or MCT4 expression is correlated with poor outcomes in human patients with head and neck squamous cell carcinoma (HNSCC). Recently, drugs targeting these transporters have been developed and may prove to be an effective treatment strategy for HNSCC. Feline oral squamous cell carcinoma (OSCC) is an aggressive and treatment‐resistant malignancy resembling advanced or recurrent HNSCC. The goals of this study were to investigate the effects of a previously characterized dual MCT1 and MCT4 inhibitor, MD‐1, in OSCC as a novel treatment approach for feline oral cancer. We also sought to determine the potential of feline OSCC as a large animal model for the further development of MCT inhibitors to treat human HNSCC. In vitro, MD‐1 reduced the viability of feline OSCC and human HNSCC cell lines, altered glycolytic and mitochondrial metabolism and synergized with platinum‐based chemotherapies. While MD‐1 treatment increased lactate concentrations in an HNSCC cell line, the inhibitor failed to alter lactate levels in feline OSCC cells, suggesting an MCT‐independent activity. In vivo, MD‐1 significantly inhibited tumour growth in a subcutaneous xenograft model and prolonged overall survival in an orthotopic model of feline OSCC. Our results show that MD‐1 may be an effective therapy for the treatment of feline oral cancer. Our findings also support the further investigation of feline OSCC as a large animal model to inform the development of MCT inhibitors and future clinical studies in human HNSCC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 19, 2019
- Source ID
- 10.1111/vco.12551
Entities
People
- Alexander G. Bush
- Ali Khammanivong
- Angela K. Spartz
- Brent S. Sorenson
- Derek M. Korpela
- Erin Dickerson
- Jhuma Saha
- Lester R Drewes
- Raj Gopalakrishnan
- Shirisha Jonnalagadda
- Timothy D. O'brien
- Venkatram R. Mereddy
Organizations
- Foundation for the National Institutes of Health
- Morris Animal Foundation
- United States Department of Defense
- University of Minnesota
- University of Minnesota College of Veterinary Medicine
- Yusuf Hamied Department of Chemistry