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Transcript of Cancer Research - Tocris Bioscience 2017-05-25آ  Cancer Research Product Guide. As cancer research...

  • Cancer Research

    Contents by Research Area: • Cancer Metabolism • Epigenetics in Cancer • Receptor Signaling • Cell Cycle and DNA Damage Repair • Angiogenesis • Invasion and Metastasis

    Autumn Crocus Colchicum autumnale A source of Colchicine

    Product Guide | Edition 3

  • Tocris Product Guide Series

    2 |

    Cancer Research

    Introduction Cancer is a major focus of research activity throughout the world. Often defined as a multifactorial disease, with genetic, epigenetic and environmental factors influencing its progression, cancer usually develops over many decades from rela- tively benign collections of cells into malignant tumors. In seminal papers written by Hanahan and Weinberg, a number of consistently observed characteristics displayed by cancer cells have been defined and were termed the ‘Hallmarks of Cancer’. These hallmarks are: sustained proliferative signaling; evasion of apoptosis and growth suppression; genomic instability; resistance to cell death; and the ability to induce angiogenesis and to metastasize.

    Over the last decade the concept of primary tumors as a collection of abnormally proliferating cells, has expanded to include important elements of the host tissue architecture and tumor microenvironment, the influence of the immune system and the presence of tumor stem cells. The mechanism by which energy metabolism is subverted in tumor cells and the study of epigenetic modifications in tumor cells are two rapidly expanding areas, which are being intensely investigated. It is with these established and emerging hallmarks of cancer in mind that we have updated the Tocris Cancer Research Product Guide.

    As cancer research progresses, the mechanisms behind malignancy are more clearly understood and additional mecha- nisms continue to come to light. Cancer researchers require both established standards and new cutting edge phar- macological tools to identify and study targets involved in these processes. Tocris provides a wide range of industry leading, high purity life science reagents for use in cancer research. Featured in each section are new and established key products, as well as a product finder, which gives a larger selection of the compounds available.

    Page Cancer Metabolism 3 Epigenetics in Cancer 8 Receptor Signaling 13 Cell Cycle and DNA Damage Repair 22 Angiogenesis 27 Invasion and Metastasis 29 Related literature 32 Cancer Research Products 33 Chemotherapeutics 59 Index 61 Further Reading 62

    Key Cancer Research Products

    Contents

    Box Number Title Page

    Box 1 Cancer Metabolism Products 6

    Box 2 Epigenetics Products 10

    Box 3 Growth Factor Receptor Products 14

    Box 4 Intracellular Signaling Products 18

    Box Number Title Page

    Box 5 Nuclear Receptor Products 20

    Box 6 Cell Cycle and DNA Damage Repair Products 24

    Box 7 Angiogenesis Products 27

    Box 8 Invasion and Metastasis Products 30

  • CANCER RESEARCH

    www.tocris.com | 3

    generated a large proportion of their ATP by metabolizing glu- cose via aerobic glycolysis (as opposed to mostly through oxi- dative phosphorylation (OXPHOS) in normal cells). Initially it was thought that this Warburg effect was a cause of cancer, but it was later established that this shift to glycolytic metabolism was an effect of cancer cell transformation. Malignant trans- formation and altered metabolism go hand in hand, because the rapid increase in proliferation places increased demand on metabolic processes that cannot be met by conventional cellu- lar metabolism. Metabolic rearrangement has been associated with inactivation of tumor suppressor genes and the activa- tion of oncogenes, as well as with abnormal mutant enzyme (oncoenzyme) activity and the accumulation of tumorigenic metabolites (oncometabolites).

    Cancer cells require three crucial metabolic adaptations in order to rapidly proliferate and survive: an increase in ATP production to fuel their high energy needs; an increased bio- synthesis of the three major classes of cellular building blocks: proteins, lipids and nucleic acids; and an adapted redox system to counteract the increase in oxidative stress (Figure 1).

    Metabolic Alterations in Cancer Cells

    Malignant transformation is associated with the following: a shift from OXPHOS to glycolysis as the main source of ATP; an increase in glucose metabolism through the pentose phos- phate pathway (PPP); an increase in lipid biosynthesis; high glutamine consumption, and alterations in pH and redox regulation (Figure 2).

    Enhanced rates of glycolysis (approximately 200-fold) place a large burden on cancer cells, which needs to be overcome in order for the cells to survive. Glycolysis produces ATP more rapidly than OXPHOS, but this process is far less efficient, so there is an increased demand for glucose. As such, glucose transporter expression is frequently increased in cancer cells

    Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared to normal cells. These dis- tinct metabolic circuits could provide viable cancer therapeutic targets. In 1924 Otto Warburg first discovered that cancer cells

    Cancer Metabolism

    Genetic and Epigenetic Alterations • Mutations in: • Oncogenes • Tumor suppressors • Enzymes

    ↑ Bioenergy • ↑ ATP production • Glycolysis dependence

    Altered Redox Balance • ↑ Buffering capacity • ↑ Transporter expression • ↑ pHi

    ↑ Biosynthesis • ↑ Proteins • ↑ Lipids • ↑ Nucleic acids

    Tumor Microenvironment • HIF-1 dynamically modulates local signaling pathways in hypoxic regions

    Abnormal cancer

    metabolism

    Figure 1 | Metabolic Alterations in Cancer

    Genetic and epigenetic mutations in cancer cells can alter the regulation of metabolic pathways. This results in increased biosynthesis, abnormal bioenergy production and an altered redox balance, all of which promotes cell proliferation and survival. Furthermore microenvironments within large tumors can dynamically alter metabolic pathways creating heterogeneous populations of cells.

    Cancer Research Target For Products See Page

    ATP-citrate Lyase (ACLY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Carbonic Anhydrases (CA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Carnitine Palmitoyltransferase (CPT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Dihydrofolate Reductase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Fatty Acid Synthase (FASN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 GAPDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Glucose Transporters (GLUT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Glutamate Dehydrogenase (GDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Glutaminase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Glutathione . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Hexokinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 HMG-CoA Reductase (HMG-CoA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Hypoxia Inducible Factor 1 (HIF-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Lactate Dehydrogenase A (LDHA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Monoacylglycerol Lipase (MAGL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Monocarboxylate Transporters (MCTs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 MutT homolog-1 (MTH1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 NAMPT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Na+/H+ Exchanger (NHE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Oxidative Phosphorylation (OXPHOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 PFKFB3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Pyruvate Dehydrogenase (PDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Pyruvate Dehydrogenase Kinase (PDK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Pyruvate Kinase M2 (PKM2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Ribonucleotide Reductase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Thymidylate Synthetase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .