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 journalArticle

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)
JournalVeterinary and Comparative Oncology
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Felidae
squamous cell carcinoma
Squamous Cell Carcinoma
mouth
cats
neoplasms
metabolism
Growth
neck
Neoplasms
transporters
Mouth Neoplasms
Lactic Acid
Therapeutics
Animal Models
Cell Line
Tumor Microenvironment
Drug Delivery Systems
lactates
Carcinoma, squamous cell of head and neck

Keywords

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

Cite this

A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma. / Khammanivong, Ali; Saha, Jhuma; Spartz, Angela K.; Sorenson, Brent S.; Bush, Alexander G.; Korpela, Derek M.; Gopalakrishnan, Raj; Jonnalagadda, Shirisha; Mereddy, Venkatram R.; O'Brien, Timothy D.; Drewes, Lester R.; Dickerson, Erin B.

In: Veterinary and Comparative Oncology, 01.01.2019.

Research output: Contribution to journalArticle

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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.",
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AU - Sorenson, Brent S.

AU - Bush, Alexander G.

AU - Korpela, Derek M.

AU - Gopalakrishnan, Raj

AU - Jonnalagadda, Shirisha

AU - Mereddy, Venkatram R.

AU - O'Brien, Timothy D.

AU - Drewes, Lester R.

AU - Dickerson, Erin B.

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