MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy
2017/09/18 by Mounia Beloueche-Babari, Mounia Beloueche‐Babari, Slawomir Wantuch +10 · 26 citations
Chemistry · Medicine · Biochemistry, Genetics and Molecular Biology · #Advanced NMR Techniques and Applications #Advanced MRI Techniques and Applications #Mitochondrial Function and Pathology
paper · pdf · doi:10.1158/0008-5472.can-16-2686
Abstract
Abstract Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle–related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by coadministration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing with AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. Cancer Res; 77(21); 5913–24. ©2017 AACR.
Citations
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- New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy
- Targeting tumor-associated acidity in cancer immunotherapy. [europepmc]
- Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma - MCT1 as potential target in diffuse large B cell lymphoma. [europepmc]
- Causes, consequences, and therapy of tumors acidosis. [europepmc]
- Monocarboxylate transporters in cancer. [europepmc]
- The Tumor Microenvironment in Colorectal Cancer Therapy. [europepmc]
- Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration. [europepmc]
- In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model. [europepmc]
- Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential. [europepmc]
- LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1. [europepmc]
- Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets. [europepmc]
- Linking Metabolic Reprogramming, Plasticity and Tumor Progression. [europepmc]
- Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review. [europepmc]
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- Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival. [europepmc]
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- Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy. [europepmc]
- In Vivo Anticancer Activity of AZD3965: A Systematic Review. [europepmc]
- Evaluation of Syrosingopine, an MCT Inhibitor, as Potential Modulator of Tumor Metabolism and Extracellular Acidification. [europepmc]
- Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context. [europepmc]
- Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. [europepmc]
- A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. [europepmc]
- Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment. [europepmc]
- Tumor microenvironmental nutrients, cellular responses, and cancer. [europepmc]
- Lactate and lactylation in cancer. [europepmc]
- Energy metabolism in health and diseases. [europepmc]
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