title: Novel aspects of mevalonate pathway inhibitors as antitumor agents.
abstract: The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as statins and bisphosphonates, inhibit mevalonate metabolism and therefore have also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. The first evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Drug-induced inhibition of protein prenylation may induce sequential cellular stress responses, including the unfolded protein response and autophagy, that eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. This review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology and contribute to tumor immune surveillance.
authors.affiliation: Cell Therapy Unit, Department of Urology, Innsbruck Medical University and K1 Center Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria. martin.thurnher@i-med.ac.at
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
authors.forename: Oliver
authors.initials: O
authors.lastname: Nussbaumer
authors.forename: Georg
authors.initials: G
authors.lastname: Gruenbacher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D054876:Prenylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors; D008798:Mevalonic Acid