Abstract
Cancer cells have a very different metabolism from that of normal cells from which they are derived. Their metabolism is elevated, which allows them to sustain higher proliferative rate and resist some cell death signals. This phenomenon, known as the “Warburg effect”, has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Both glycolysis and glutaminolysis pathways are enhanced in cancer cells. While glycolysis is enhanced to satisfy the increasing energy demand of cancer cells, glutaminolysis is enhanced to provide biosynthetic precursors for cancer cells. It was recently discovered that there is a tyrosine phosphorylation of a specific isoform of pyruvate kinase, the M2 isoform, that is preferentially expressed in all cancer cells, which results in the generation of pyruvate through a unique enzymatic mechanism that is uncoupled from ATP production. Pyruvate produced through this unique enzymatic mechanism is converted primarily into lactic acid, rather than acetyl-CoA for the synthesis of citrate, which would normally then enter the citric acid cycle. Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials. This review paper will cover recent advances in the development of chemotherapeutic agents against several metabolic targets for cancer therapy, including glucose transporters, hexokinase, pyruvate kinase M2, glutaminase, and isocitrate dehydrogenase.
Keywords: Cancer, glycolysis, glutaminolysis, hexokinase, glucose transporters, pyruvate kinase M2, glutaminase, isocitrate dehydrogenase.
Current Topics in Medicinal Chemistry
Title:Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer
Volume: 18 Issue: 6
Author(s): Nicholas S. Akins, Tanner C. Nielson and Hoang V. Le*
Affiliation:
- Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677,United States
Keywords: Cancer, glycolysis, glutaminolysis, hexokinase, glucose transporters, pyruvate kinase M2, glutaminase, isocitrate dehydrogenase.
Abstract: Cancer cells have a very different metabolism from that of normal cells from which they are derived. Their metabolism is elevated, which allows them to sustain higher proliferative rate and resist some cell death signals. This phenomenon, known as the “Warburg effect”, has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Both glycolysis and glutaminolysis pathways are enhanced in cancer cells. While glycolysis is enhanced to satisfy the increasing energy demand of cancer cells, glutaminolysis is enhanced to provide biosynthetic precursors for cancer cells. It was recently discovered that there is a tyrosine phosphorylation of a specific isoform of pyruvate kinase, the M2 isoform, that is preferentially expressed in all cancer cells, which results in the generation of pyruvate through a unique enzymatic mechanism that is uncoupled from ATP production. Pyruvate produced through this unique enzymatic mechanism is converted primarily into lactic acid, rather than acetyl-CoA for the synthesis of citrate, which would normally then enter the citric acid cycle. Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials. This review paper will cover recent advances in the development of chemotherapeutic agents against several metabolic targets for cancer therapy, including glucose transporters, hexokinase, pyruvate kinase M2, glutaminase, and isocitrate dehydrogenase.
Export Options
About this article
Cite this article as:
Akins S. Nicholas , Nielson C. Tanner and Le V. Hoang *, Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer, Current Topics in Medicinal Chemistry 2018; 18 (6) . https://dx.doi.org/10.2174/1568026618666180523111351
DOI https://dx.doi.org/10.2174/1568026618666180523111351 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization
Mini-Reviews in Medicinal Chemistry Fluoxetine and all other SSRIs are 5-HT<sub>2B</sub> Agonists - Importance for their Therapeutic Effects
Current Neuropharmacology Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions
Current Pharmaceutical Design Interaction of Endocannabinoid Receptors with Biological Membranes
Current Medicinal Chemistry Fluorescence Imaging of Human Cells with a Novel Conjugate of the Antifungal Nystatin
Medicinal Chemistry Aquaporins and Roles in Brain Health and Brain Injury
Mini-Reviews in Medicinal Chemistry Current Development in Encapsulated Cell Therapy for Degenerative Retinopathies
Current Tissue Engineering (Discontinued) Impact of Oncogenic Protein Tyrosine Phosphatases in Cancer
Anti-Cancer Agents in Medicinal Chemistry Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells
Anti-Cancer Agents in Medicinal Chemistry Human Cytomegalovirus US28: A Functionally Selective Chemokine Binding Receptor
Infectious Disorders - Drug Targets The Possibility of Novel Antiplatelet Peptides: The Physiological Effects of Low Molecular Weight HSPs on Platelets
Current Pharmaceutical Design Serum Carboxypeptidase N1 Serves as a Potential Biomarker Complementing CA15-3 for Breast Cancer
Anti-Cancer Agents in Medicinal Chemistry Bcl-2 Inhibitors: Emerging Drugs in Cancer Therapy
Current Medicinal Chemistry Pentacyclic Triterpenoids and Their Saponins with Apoptosis-Inducing Activity
Current Topics in Medicinal Chemistry Medicinal Chemistry of Indolylglyoxylamide TSPO High Affinity Ligands with Anxiolytic-Like Effects
Current Topics in Medicinal Chemistry Structure-Based Design of Benzimidazole Sugar Conjugates: Synthesis, SAR and In Vivo Anti-inflammatory and Analgesic Activities
Medicinal Chemistry Hemisynthesis of Selected Embelin Analogs and Investigation of their Proapoptotic Activity Against Cancer Cells
Medicinal Chemistry Prostaglandin J2 Family and the Cardiovascular System
Current Vascular Pharmacology The Autism Candidate Gene Neurobeachin Encodes a Scaffolding Protein Implicated in Membrane Trafficking and Signaling
Current Molecular Medicine Fibroblast Growth Factor-2 Antagonist and Antiangiogenic Activity of Long-Pentraxin 3-Derived Synthetic Peptides
Current Pharmaceutical Design