A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma

Ali Khammanivong, Jhuma Saha, Angela K. Spartz, Brent S. Sorenson, Alexander G. Bush, Derek M. Korpela, Raj Gopalakrishnan, Shirisha Jonnalagadda, Venkatram R. Mereddy, Timothy D. O'Brien, Lester R. Drewes, Erin B. Dickerson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)324-341
Number of pages18
JournalVeterinary and Comparative Oncology
Volume18
Issue number3
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
This work was supported by grant D15FE‐020 from Morris Animal Foundation (E.B.D., T.D.O. and L.R.D.), the Comparative Medicine Signature Program of the College of Veterinary Medicine, University of Minnesota (E.B.D., T.D.O. and L.R.D) and the Department of Defense grants W81XWH‐15‐1‐0047 (V.R.M) and W81XWH‐15‐1‐0060 (L.R.D.). The National Institutes of Health (NIH) Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota (P30 CA077598) provided support for genomics, bioimaging and comparative pathology services. The authors gratefully acknowledge donations to the Animal Cancer Care and Research Program of the University of Minnesota that helped support this project.

Keywords

  • Feline oral squamous cell carcinoma
  • Head and neck cancer
  • MCT1
  • MCT4
  • metabolic coupling
  • metabolism

PubMed: MeSH publication types

  • Journal Article

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