The progress and development of GLUT1 inhibitors targeting cancer energy metabolism

A major difference between glucose metabolism in cancer cells and normal cells is that glucose in cancer cells is preferably converted to lactate in aerobic conditions rather than oxidized in mitochondria. This process is called aerobic glycolysis, known as the ‘Warburg effect’. In this review, we focus on the energy-metabolism characteristics between tumor and normal cells, analyzing the regulation mechanism of energy metabolism based on glycolysis, and summarizing two targets on the upstream proteins of glycolysis, including glucose transporter (GLUT) and hexokinase. In addition, we proposed the risks and limitations of GLUT1-based drug research and summarized the current research progress of representative drugs, including natural and synthetic GLUT1 inhibitors. This will provide guidance for designing and synthesizing small molecule drugs targeting GLUT1 in glycolysis.

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Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

Pharmaceuticals ◽

10.3390/ph14101060 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1060

Author(s):

Kyoung Song ◽

Nirmal Rajasekaran ◽

Chaithanya Chelakkot ◽

Hunseok Lee ◽

Seungmann Paek ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Fumarate Hydratase ◽

Metabolic Adaptation ◽

Normal Cells ◽

Target Proteins ◽

Anti Cancer ◽

The Warburg Effect

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Cancers ◽

10.3390/cancers13215557 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5557

Author(s):

Alexandre Vallée ◽

Yves Lecarpentier ◽

Jean-Noël Vallée

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Warburg Effect ◽

Target Genes ◽

Glucose Transporter ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Metabolic Reprogramming ◽

Pyruvate Dehydrogenase Kinase ◽

The Warburg Effect

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

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Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

International Journal of Molecular Sciences ◽

10.3390/ijms21051661 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1661

Author(s):

Anamarija Mojzeš ◽

Marko Tomljanović ◽

Lidija Milković ◽

Renata Novak Kujundžić ◽

Ana Čipak Gašparović ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Intracellular Localization ◽

Lactate Production ◽

Glucose Consumption ◽

Cell Type ◽

Cell Type Specific ◽

The Warburg Effect

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.

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The Warburg effect: 80 years on

Biochemical Society Transactions ◽

10.1042/bst20160094 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1499-1505 ◽

Cited By ~ 155

Author(s):

Michelle Potter ◽

Emma Newport ◽

Karl J. Morten

Keyword(s):

Cancer Cells ◽

High Glucose ◽

Warburg Effect ◽

Energy Requirement ◽

Glucose Consumption ◽

High Energy ◽

Metabolic Reprogramming ◽

Normal Cells ◽

Cancer Types ◽

The Warburg Effect

Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

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Emerging Glycolysis Targeting and Drug Discovery from Chinese Medicine in Cancer Therapy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/873175 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Zhiyu Wang ◽

Neng Wang ◽

Jianping Chen ◽

Jiangang Shen

Keyword(s):

Drug Discovery ◽

Chinese Medicine ◽

Herbal Medicine ◽

Cancer Treatment ◽

Cancer Cells ◽

Warburg Effect ◽

Glycolytic Pathway ◽

Normal Cells ◽

Active Compounds ◽

The Warburg Effect

Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the “Warburg Effect.” Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM) is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment.

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Retraction: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgz056 ◽

2019 ◽

Vol 40 (2) ◽

pp. e16-e16

Author(s):

I-Lu Lai ◽

Chih-Chien Chou ◽

Po-Ting Lai ◽

Chun-Sheng Fang ◽

Lawrence A Shirley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

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MicroRNA-124 suppresses proliferation and glycolysis in non–small cell lung cancer cells by targeting AKT–GLUT1/HKII

Tumor Biology ◽

10.1177/1010428317706215 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770621 ◽

Cited By ~ 34

Author(s):

Xiaojian Zhao ◽

Caiping Lu ◽

Weiwei Chu ◽

Bing Zhang ◽

Qiang Zhen ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Energy Metabolism ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Glucose Transporter ◽

Small Cell ◽

Small Cell Lung ◽

Glucose Transporter 1

Non–small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non–small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non–small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD+/NADH were also detected. These tests were conducted using the normal non–small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate–limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non–small cell lung cancer. AKT inhibition blocks miR-124 silencing–induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2–glucose transporter 1/hexokinase II in non–small cell lung cancer cells.

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Pieces of the complex puzzle of cancer cell energy metabolism: an overview of energy metabolism and alternatives for targeted cancer therapy

Current Medicinal Chemistry ◽

10.2174/0929867327999200819123357 ◽

2020 ◽

Vol 27 ◽

Author(s):

Zeinab Ghasemishahrestani ◽

Larissa Maura Melo Mattos ◽

Tatiana Martins Tilli ◽

André Souza dos Santos ◽

Marcos Dias Pereira

Keyword(s):

Energy Metabolism ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Warburg Effect ◽

Cell Biology ◽

Aerobic Glycolysis ◽

Target Therapy ◽

Cell Metabolism ◽

Cancer Cell Metabolism

Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called "Warburg effect". Currently, it has been accepted that Warburg effect is not anymore compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused in the bioenergetic and biosynthetic pathways to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrate, amino acids and lipids have already been reported in cancer cells and might play relevant roles for cancer progression. To the best of our knowledge, mostly of these changes are established, mainly due to genetic reprogramming that leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes of high relevance for the energy are targets of oncogenes (ex. PI3K, HIF1 and Myc) and tumor suppressor proteins (ex. p53). As a consequence of the extensive study on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, as well as the influence of genetic reprogramming in cancer cells. In this perspective, we briefly review the cancer cell metabolism (carbohydrate, amino acid and lipid), and also describe oncogenes and tumor suppressors that affect cancer cell metabolism. We also discuss some potential candidates for target therapy to disrupt the main driven-force for cancer cell metabolism and proliferation.

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RETRACTED: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgu124 ◽

2014 ◽

Vol 35 (10) ◽

pp. 2203-2213 ◽

Cited By ~ 25

Author(s):

I-Lu Lai ◽

Chih-Chien Chou ◽

Po-Ting Lai ◽

Chun-Sheng Fang ◽

Lawrence A Shirley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

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Thermodynamic Modeling of the Competition Between Cancer and Normal Cells

Journal of Non-Equilibrium Thermodynamics ◽

10.1515/jnet-2019-0037 ◽

2020 ◽

Vol 45 (1) ◽

pp. 19-25

Author(s):

Mostafa Sadeghi Ghuchani

Keyword(s):

Cancer Cells ◽

Entropy Production ◽

Production Rate ◽

Thermodynamic Model ◽

Warburg Effect ◽

Entropy Production Rate ◽

Metabolic Efficiency ◽

Normal Cells ◽

Functional Explanations ◽

The Warburg Effect

AbstractOne of the recognized differences between normal and cancer cells is in their metabolic profile. Tumor cells tend to produce energy through glycolysis rather than the much more efficient oxidative phosphorylation pathway, which healthy cells generally prefer. This phenomenon is identified as the Warburg effect. Although several functional explanations have been proposed for the Warburg effect, the competitive advantage of it is still subject of debate. Here we present a thermodynamic model to simulate the competition of cancer and normal cells in terms of bioenergetics. Our model shows that the Warburg effect has an advantage because the entropy production rate is increased and metabolic efficiency is decreased for cancer cells. Although inefficiency is generally considered a competitive disadvantage for living organisms, the thermodynamic model shows that it is not always the case. Indeed, when the energy resources are abundant and the system has a limited ability to export entropy, the organism with a higher rate of entropy production will have a higher chance of survival despite its lower metabolic efficiency. This thermodynamic model predicts that as long as there are enough nutrients in circulating blood, there are two thermodynamic strategies to control cancer cell populations, i. e., (i) decreasing the entropy production rate of cancer cells and (ii) increasing normal cells’ entropy production rate.

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