A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2516-2516 ◽  
Author(s):  
Sarah E. R. Halford ◽  
Paul Jones ◽  
Steve Wedge ◽  
Sandra Hirschberg ◽  
Sidath Katugampola ◽  
...  
Keyword(s):  
Receptor Occupancy ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Monocarboxylate Transporter ◽  
Cancer Cell Growth ◽  
Monocarboxylate Transporter 1 ◽  
History Of ◽  
Target Effect ◽  
Dose Levels

2516 Background: A key metabolic alteration in tumour cells is an increased dependency on the glycolysis, resulting in the production of lactate, which is transported out of cells by MCTs. Inhibition of MCT-1 leads to a profound inhibition of cancer cell growth in preclinical models. AZD3965 is a FIC inhibitor of MCT-1, and we report results from the phase I study of this agent. Methods: Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake; plasma/urine metabolomics and MCT-1 and MCT-4 tumour expression by immunohistochemistry. Results: 35 patients (20M:15F median age 65) were treated at dose levels 5, 10, 20, and 30mg od and 15 and 10mg bd. AZD3965 was generally well tolerated with nausea and fatigue (CTCAE Gr1-2) the most commonly reported side effects. A single DLT of cardiac troponin rise was observed at 20mg od. Asymptomatic, reversible retinal ERG changes were observed in all but the lowest dose levels, with DLTs observed at doses above 20mg od. PK data indicate exposures in the preclinical efficacy range. Metabolomic changes in urinary lactate and urinary ketones correlate with on-target activity. The increase in urinary ketones is likely to be attributable to the role of MCT1 in physiological ketone transport. Conclusions: The MCT1 inhibitor AZD3965 can be administered to patients at doses which engage the drug target, with a MTD of 20mg od po. DLTs seen were primarily dose dependent, asymptomatic and reversible changes in retinal function, which were an expected on-target effect. Investigation of the activity of AZD3965 is ongoing in tumours known to express MCT1. Clinical trial information: NCT01791595.

scholarly journals Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1

2000 ◽  
Vol 279 (4) ◽  
pp. G775-G780 ◽  
Author(s):  
Christos Hadjiagapiou ◽  
Larry Schmidt ◽  
Pradeep K. Dudeja ◽  
Thomas J. Layden ◽  
Krishnamurthy Ramaswamy
Keyword(s):  
Short Chain Fatty Acid ◽  
Rnase Protection Assay ◽  
Significant Inhibition ◽  
Monocarboxylate Transporter ◽  
Rnase Protection ◽  
Monocarboxylate Transporter 1 ◽  
Antisense Orientation ◽  
Transporter Family ◽  
Saturation Kinetics

The short-chain fatty acid butyrate was readily taken up by Caco-2 cells. Transport exhibited saturation kinetics, was enhanced by low extracellular pH, and was Na+independent. Butyrate uptake was unaffected by DIDS; however, α-cyano-4-hydroxycinnamate and the butyrate analogs propionate and l-lactate significantly inhibited uptake. These results suggest that butyrate transport by Caco-2 cells is mediated by a transporter belonging to the monocarboxylate transporter family. We identified five isoforms of this transporter, MCT1, MCT3, MCT4, MCT5, and MCT6, in Caco-2 cells by PCR, and MCT1 was found to be the most abundant isoform by RNase protection assay. Transient transfection of MCT1, in the antisense orientation, resulted in significant inhibition of butyrate uptake. The cells fully recovered from this inhibition by 5 days after transfection. In conclusion, our data showed that the MCT1 transporter may play a major role in the transport of butyrate into Caco-2 cells.

scholarly journals D-Lactate Increases Cytokine Production in Bovine Fibroblast-Like Synoviocytes via MCT1 Uptake and the MAPK, PI3K/Akt, and NFκB Pathways

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2105
Author(s):  
Carolina Manosalva ◽  
John Quiroga ◽  
Stefanie Teuber ◽  
Sebastián Cárdenas ◽  
María Daniella Carretta ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Inflammatory Responses ◽  
Monocarboxylate Transporter ◽  
Dependent Manner ◽  
Monocarboxylate Transporter 1 ◽  
Ruminal Acidosis ◽  
Excessive Intake ◽  
Fermentable Carbohydrates ◽  
Fibroblast Like Synoviocytes

Acute ruminal acidosis (ARA) is caused by the excessive intake of highly fermentable carbohydrates, followed by the massive production of D-lactate and the appearance of neutrophilic aseptic polysynovitis. Bovines with ARA develop different lesions, such as ruminitis, polioencephalomalacia (calves), liver abscess and lameness. Lameness in cattle with ARA is closely associated with the presence of laminitis and polysynovitis. However, despite decades of research in bovine lameness as consequence of ruminal acidosis, the aetiology and pathogenesis remain unclear. Fibroblast-like synoviocytes (FLSs) are components of synovial tissue, and under pathological conditions, FLSs increase cytokine production, aggravating inflammatory responses. We hypothesized that D-lactate could induce cytokine production in bovine FLSs. Analysis by qRT-PCR and ELISA revealed that D-lactate, but not L-lactate, increased the expression of IL-6 and IL-8 in a monocarboxylate transporter-1-dependent manner. In addition, we observed that the inhibition of the p38, ERK1/2, PI3K/Akt, and NF-κB pathways reduced the production of IL-8 and IL-6. In conclusion, our results suggest that D-lactate induces an inflammatory response; this study contributes to the literature by revealing a potential key role of D-lactate in the polysynovitis of cattle with ARA.

Monocarboxylate Transporter 1 in Brain Diseases and Cancers

2019 ◽  
Vol 20 (11) ◽  
pp. 855-866 ◽  
Author(s):  
Yixin Sun ◽  
Jin Sun ◽  
Zhonggui He ◽  
Gang Wang ◽  
Yang Wang ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Monocarboxylate Transporter ◽  
Brain Diseases ◽  
General Description ◽  
Monocarboxylate Transporter 1 ◽  
Diagnosis Of Cancer ◽  
Basic Characteristics ◽  
The Brain ◽  
Proliferation And Invasion

Background: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. Methods: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. Results: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. Conclusion: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.

scholarly journals Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells

2015 ◽  
Vol 309 (7) ◽  
pp. G602-G607 ◽  
Author(s):  
Anoop Kumar ◽  
Waddah A. Alrefai ◽  
Alip Borthakur ◽  
Pradeep K. Dudeja
Keyword(s):  
Cell Surface ◽  
Intestinal Inflammation ◽  
Apical Cell ◽  
Monocarboxylate Transporter ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Monocarboxylate Transporter 1 ◽  
E Coli ◽  
Fatty Acid Metabolite

Butyrate, a key short-chain fatty acid metabolite of colonic luminal bacterial action on dietary fiber, serves as a primary fuel for the colonocytes, ameliorates mucosal inflammation, and stimulates NaCl absorption. Absorption of butyrate into the colonocytes is essential for these intracellular effects. Monocarboxylate transporter 1 (MCT1) plays a major role in colonic luminal butyrate absorption. Previous studies (Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. Adv Immunol 121: 91–119, 2014.) showed decreased MCT1 expression and function in intestinal inflammation. We have previously shown (Borthakur A, Gill RK, Hodges K, Ramaswamy K, Hecht G, Dudeja PK. Am J Physiol Gastrointest Liver Physiol 290: G30–G35, 2006.) impaired butyrate absorption in human intestinal epithelial Caco-2 cells due to decreased MCT1 level at the apical cell surface following enteropathogenic E. coli (EPEC) infection. Current studies, therefore, examined the potential role of probiotic Lactobacilli in stimulating MCT1-mediated butyrate uptake and counteracting EPEC inhibition of MCT1 function. Of the five species of Lactobacilli, short-term (3 h) treatment with L. acidophilus (LA) significantly increased MCT1-mediated butyrate uptake in Caco-2 cells. Heat-killed LA was ineffective, whereas the conditioned culture supernatant of LA (LA-CS) was equally effective in stimulating MCT1 function, indicating that the effects are mediated by LA-secreted soluble factor(s). Furthermore, LA-CS increased apical membrane levels of MCT1 protein via decreasing its basal endocytosis, suggesting that LA-CS stimulation of butyrate uptake could be secondary to increased levels of MCT1 on the apical cell surface. LA-CS also attenuated EPEC inhibition of butyrate uptake and EPEC-mediated endocytosis of MCT1. Our studies highlight distinct role of specific LA-secreted molecules in modulating colonic butyrate absorption.

scholarly journals Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes

2020 ◽  
pp. jbc.RA120.016303
Author(s):  
Damien LAGARDE ◽  
Yannick JEANSON ◽  
Corinne BARREAU ◽  
Cedric Moro ◽  
Lindsay PEYRIGA ◽  
...  
Keyword(s):  
Metabolic Activity ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Monocarboxylate Transporter ◽  
Monocarboxylate Transporter 1 ◽  
Isotopic Tracing ◽  
Beige Adipocytes ◽  
Metabolic Conditions

Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation of Ucp1 gene expression, the role of lactate transporters on beige adipocytes’ ongoing metabolic activity remains poorly understood. To explore the function of the lactate-transporting monocarboxylate transporters (MCTs), we used a combination of primary cell culture studies, 13C isotopic tracing, laser microdissection experiments and in situ immunofluorescence of murine adipose fat pads. Dissecting white adipose tissue heterogeneity revealed that the MCT1 is expressed in inducible beige adipocytes as the emergence of uncoupling protein-1 after cold exposure was restricted to a subpopulation of MCT1 expressing adipocytes suggesting MCT1 as a marker of inducible beige adipocytes. We also observed that MCT1 mediates bidirectional and simultaneous inward and outward lactate fluxes which were required for efficient utilization of glucose by beige adipocytes activated by the canonical β3-adrenergic signaling pathway. Finally, we demonstrated that significant lactate import through MCT1 occurs even when glucose is not limiting, that feeds the oxidative metabolism of beige adipocytes. These data highlight the key role of lactate fluxes in finely tuning beige adipocytes metabolic activity according to extracellular metabolic conditions and reinforce the emerging role of lactate metabolism in the control of energy homeostasis.

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