Abstract
Tumor cells respond to growth signals by the activation of protein kinases, altered gene expression and significant modifications in substrate flow and re-distribution among biosynthetic pathways. This results in a proliferating phenotype with altered cellular function. These transformed cells exhibit unique anabolic characteristics, which includes increased and preferential utilization of glucose through the non-oxidative steps of the pentose cycle for nucleic acid synthesis but limited de novo fatty acid synthesis and TCA cycle glucose oxidation. This primarily non-oxidative anabolic profile reflects an undifferentiated highly proliferative aneuploid cell phenotype and serves as a reliable metabolic biomarker to determine cell proliferation rate and the level of cell transformation / differentiation in response to drug treatment. Novel drugs effective in particular cancers exert their anti-proliferative effects by inducing significant reversions of a few specific non-oxidative anabolic pathways. Here we present evidence that cell transformation of various mechanisms is sustained by a unique disproportional substrate distribution between the two branches of the pentose cycle for nucleic acid synthesis, glycolysis and the TCA cycle for fatty acid synthesis and glucose oxidation. This can be demonstrated by the broad labeling and unique specificity of [1,2-13C2]glucose to trace a large number of metabolites in the metabolome. Stable isotope-based dynamic metabolic profiles (SIDMAP) serve the drug discovery process by providing a powerful new tool that integrates the metabolome into a functional genomics approach to developing new drugs. It can be used in screening kinases and their metabolic targets, which can therefore be more efficiently characterized, speeding up and improving drug testing, approval and labeling processes by saving trial and error type study costs in drug testing.
Keywords: metabolic biomarker, kinase drug target discovery, stable isotope-based dynamic metabolic profiling, fatty acid synthesis, anti-proliferative effects, disproportional substrate, metabolome
Current Cancer Drug Targets
Title: Metabolic Biomarker and Kinase Drug Target Discovery in Cancer Using Stable Isotope-Based Dynamic Metabolic Profiling (SIDMAP)
Volume: 3 Issue: 6
Author(s): Laszlo G. Boros, Daniel J. Brackett and George G. Harrigan
Affiliation:
Keywords: metabolic biomarker, kinase drug target discovery, stable isotope-based dynamic metabolic profiling, fatty acid synthesis, anti-proliferative effects, disproportional substrate, metabolome
Abstract: Tumor cells respond to growth signals by the activation of protein kinases, altered gene expression and significant modifications in substrate flow and re-distribution among biosynthetic pathways. This results in a proliferating phenotype with altered cellular function. These transformed cells exhibit unique anabolic characteristics, which includes increased and preferential utilization of glucose through the non-oxidative steps of the pentose cycle for nucleic acid synthesis but limited de novo fatty acid synthesis and TCA cycle glucose oxidation. This primarily non-oxidative anabolic profile reflects an undifferentiated highly proliferative aneuploid cell phenotype and serves as a reliable metabolic biomarker to determine cell proliferation rate and the level of cell transformation / differentiation in response to drug treatment. Novel drugs effective in particular cancers exert their anti-proliferative effects by inducing significant reversions of a few specific non-oxidative anabolic pathways. Here we present evidence that cell transformation of various mechanisms is sustained by a unique disproportional substrate distribution between the two branches of the pentose cycle for nucleic acid synthesis, glycolysis and the TCA cycle for fatty acid synthesis and glucose oxidation. This can be demonstrated by the broad labeling and unique specificity of [1,2-13C2]glucose to trace a large number of metabolites in the metabolome. Stable isotope-based dynamic metabolic profiles (SIDMAP) serve the drug discovery process by providing a powerful new tool that integrates the metabolome into a functional genomics approach to developing new drugs. It can be used in screening kinases and their metabolic targets, which can therefore be more efficiently characterized, speeding up and improving drug testing, approval and labeling processes by saving trial and error type study costs in drug testing.
Export Options
About this article
Cite this article as:
Boros G. Laszlo, Brackett J. Daniel and Harrigan G. George, Metabolic Biomarker and Kinase Drug Target Discovery in Cancer Using Stable Isotope-Based Dynamic Metabolic Profiling (SIDMAP), Current Cancer Drug Targets 2003; 3 (6) . https://dx.doi.org/10.2174/1568009033481769
DOI https://dx.doi.org/10.2174/1568009033481769 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
FDG-PET/CT Imaging of Infected Bones and Prosthetic Joints
Current Molecular Imaging (Discontinued) Antitumor Properties of Natural Compounds and Related Molecules
Recent Patents on Anti-Cancer Drug Discovery Lipidomic Analysis of Glioblastoma Multiforme Using Mass Spectrometry
Current Metabolomics Discovery of Potent Bruton’s Tyrosine Kinase Inhibitors Using Ligand Based Modeling
Anti-Cancer Agents in Medicinal Chemistry Peptide-Mediated Cellular Delivery of Oligonucleotide-Based Therapeutics In Vitro: Quantitative Evaluation of Overall Efficacy Employing Easy to Handle Reporter Systems
Current Pharmaceutical Design Cytochrome P450 2W1 (CYP2W1) in Colorectal Cancers
Current Cancer Drug Targets Editorial (Thematic Issue: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets – Part II)
Current Molecular Pharmacology Recent Advances and Future Directions in the Management of Metastatic Renal Cell Carcinoma
Anti-Cancer Agents in Medicinal Chemistry Mucosal Vaccines: Where Do We Stand?
Current Topics in Medicinal Chemistry Design, Synthesis, In vitro Cytotoxic Activity Evaluation, and Study of Apoptosis Inducing Effect of New Styrylimidazo[1,2-a]Pyridines as Potent Anti-Breast Cancer Agents
Anti-Cancer Agents in Medicinal Chemistry An Efficient Four-Step Approach Toward Fused Triazino[1,6-a] Quinazolines
Combinatorial Chemistry & High Throughput Screening Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters for Designing Good Quality Films
Current Applied Polymer Science The Diagnostic and Prognostic Value of Brain Natriuretic Peptide and Aminoterminal (nt)-pro Brain Natriuretic Peptide
Current Pharmaceutical Design Exploring Nanotechnologies for the Effective Therapy of Malaria Using Plant-Based Medicines
Current Pharmaceutical Design Pathobiology of Head and Neck Squamous Tumorigenesis
Current Cancer Drug Targets ABCB1, SLCO1B1 and UGT1A1 Gene Polymorphisms Are Associated with Toxicity Line Irinotecan
Drug Metabolism Letters Strategies for Developing Tuberculosis Vaccines: Emerging Approaches
Current Drug Targets Restoration of Transgene Expression in Hematopoietic Cells with Drug-Selectable Marker Genes
Current Gene Therapy Targeting miRNAs for Pancreatic Cancer Therapy
Current Pharmaceutical Design Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design
Anti-Cancer Agents in Medicinal Chemistry