Targeting the mevalonate pathway for improved anticancer therapy.
The mevalonate pathway is important for the generation of isoprene moieties thereby providing the basis for the biosynthesis of molecules required for maintaining membrane integrity, steroid production and cell respiration. Additionally, isoprene precursors are indispensable for the prenylation of regulatory proteins such as Ras and Ras-homologous (Rho) GTPases. These low molecular GTP-binding proteins play key roles in numerous signal transduction pathways stimulated upon activation of cell surface receptors by ligand binding. Thus, Ras/Rho proteins eventually regulate cell proliferation, tumor progression and cell death induced by anticancer therapeutics. Lipid modification of Ras/Rho proteins at their C-terminal CAAX-box is essential for their correct intracellular localization and function. Therefore, pharmacological inhibition of the isoprene metabolism is anticipated to impact the manifold biological functions attributed to Ras/Rho proteins. Here, the pros and cons of compounds that interfere with the mevalonate pathway for cancer treatment are summarized and discussed.
Fritz
G
G
Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany. fritz@uni-mainz.de
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D055808:Drug Discovery; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; C109563:RTL8C protein, human; D004122:Dimethylallyltranstransferase; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid