Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells

Saulle, Ernestina; Spinello, Isabella; Quaranta, Maria Teresa; Pasquini, Luca; Iorio, Egidio; Castelli, Germana; Chirico, Mattea; Pisanu, Maria Elena; Ottone, Tiziana; Voso, Maria Teresa; Testa, Ugo; Labbaye, Catherine

doi:10.3389/fonc.2020.621458

Cited by 32 publications

(31 citation statements)

References 47 publications

(111 reference statements)

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“…For example, 7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid (7ACC2) is a potent inhibitor of MCT1 and mitochondrial pyruvate transport that has been reported to be effective in multiple human cancer types [ 91 , 92 ]. Other novel small-molecule inhibitors, including AR-C155858, AZD3965, and BAY-8002, have demonstrated potent MCT1-inhibitory and immunomodulatory activities [93] , [94] , [95] , [96] , [97] . Moreover, most of these MCT1 inhibitors are also active against MCT2 [90] .…”

Section: Lactate In the Tmementioning

confidence: 99%

Lactate in the tumour microenvironment: From immune modulation to therapy

et al. 2021

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Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

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Section: Lactate In the Tmementioning

confidence: 99%

Lactate in the tumour microenvironment: From immune modulation to therapy

et al. 2021

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“…AR-C155858 and syrosingopine act on lactate metabolism by blocking MCT1 and MCT4 transporters, which remove the excess lactate produced by cancer cells. The lactate transporter MCT4 has been identified as a transcriptional target of HIF-1α [112] and a study from Saulle et al demonstrated that in AML patients MCT4 overexpression is associated with poor prognosis [113]. In addition, AR-C155858 and syrosingopine exert anti-proliferative effects on AML cell lines that showed increased intracellular lactate level and enhanced the sensitivity of AML cell lines to Ara-C treatment [113].…”

Section: Targeting Altered Metabolismmentioning

confidence: 99%

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Bruno

Mancini

Santis

et al. 2021

IJMS

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Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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“…Despite this, diclofenac (a well-known nonsteroidal anti-inflammatory drug) behaves as a strong, non-competitive inhibitor of monocarboxylate transport [ 31 ]. Recently, it has been proposed that MCT4 can be a potential therapeutic target in leukemic patients and that some of its inhibitors can serve as a new anti-proliferative drug in combination with conventional chemotherapeutic agents [ 32 ]. Our data reinforce the possible association of MCT4 and malignancy in breast cancer by the observation from patient samples that the expression of this MCT4 was also differentially expressed in the epithelial compartment of tumors of a different Elston Grade ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

et al. 2021

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Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

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Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells

Cited by 32 publications

References 47 publications

Lactate in the tumour microenvironment: From immune modulation to therapy

Lactate in the tumour microenvironment: From immune modulation to therapy

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

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