In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model


Monocarboxylate transporter 1 (MCT1), also known as a l-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression. AR-C155858 inhibited the cellular l-lactate uptake and cellular proliferation at low nanomolar potencies (IC50 values of 25.0 ± 4.2 and 20.2 ± 0.2 nM, respectively). In the xenograft 4T1 mouse model of immunocompetent animals, AR-C155858 (10 mg/kg i.p. once daily) had no effect on tumor volume and weight. Treatment with AR-C155858 resulted in slightly increased tumor lactate concentrations; however, the changes were not statistically significant. AR-C155858 was well tolerated, as demonstrated by the unchanged body weight and blood lactate concentrations. Average blood and tumor AR-C155858 concentrations (110 ± 22 and 574 ± 245 nM, respectively), 24 h after the last dose, were well above the IC50 values. These data indicate that AR-C155858 penetrated 4T1 xenograft tumors and was present at high concentrations but was ineffective in decreasing tumor growth. Evaluations of AR-C155858 in other preclinical models of breast cancer are needed to further assess its efficacy.

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Monocarboxylate transporters


Triple negative breast cancer




Estrogen receptor


Progesterone receptor


Human epidermal growth factor receptor 2


Gamma-hydroxybutyric acid


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We thank Donna Ruszaj for her assistance in the LC/MS/MS.


This work was funded by the National Institute of Health National Institute on Drug Abuse (grant DA023223). X.G. was funded in part by Allen Barnett Fellowship.

Author information




Participated in research design: Guan and Morris

Conducted experiments: Guan and Bryniarski

Contributed new reagents or analytic tools: Guan and Morris

Performed data analysis: Guan and Morris

Wrote or contributed to the writing of the manuscript: Guan and Morris

Corresponding author

Correspondence to Marilyn E. Morris.

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All animal protocols were approved by the Institutional Animal Care and Use Committee at the University at Buffalo.

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Guan, X., Bryniarski, M.A. & Morris, M.E. In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model. AAPS J 21, 3 (2019).

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  • AR-C155858
  • breast cancer
  • monocarboxylate transporter 1
  • 4T1