title: Death receptor pathway activation and increase of ROS production by the triple epigenetic inhibitor UVI5008.
abstract: Deregulation of the epigenome is recognized as cause of cancer and epigenetic factors are receiving major attention as therapeutic targets; yet, the molecular mode of action of existing epi-drugs is largely elusive. Here, we report on the decryption of the mechanism of action of UVI5008, a novel epigenetic modifier, that inhibits histone deacetylases, sirtuins, and DNA methyltransferases. UVI5008 highly efficiently induces cancer cell-selective death in a variety of models and exerts its activities in several human tumor xenografts and genetic mouse models of human breast cancer in vivo. Its anticancer activity involves independent activation of death receptors and reactive oxygen species production. Importantly, UVI5008 action is not critically dependent on p53, Bcl-2 modifying factor, and/or TNF-related apoptosis-inducing ligand as cell death is efficiently induced in cells mutated or deficient for these factors limiting the risk of drug resistance development and maximizing its application spectrum. The simultaneous modulation of multiple (epigenetic) targets promises to open new avenues with unanticipated potential against cancer.
authors: Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy.
authors: Angela
authors: A
authors: Nebbioso
authors: Raquel
authors: R
authors: Pereira
authors: Harshal
authors: H
authors: Khanwalkar
authors: Filomena
authors: F
authors: Matarese
authors: José
authors: J
authors: García-Rodríguez
authors: Marco
authors: M
authors: Miceli
authors: Colin
authors: C
authors: Logie
authors: Valerie
authors: V
authors: Kedinger
authors: Felicetto
authors: F
authors: Ferrara
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: Angel R
authors: AR
authors: de Lera
authors: Hinrich
authors: H
authors: Gronemeyer
authors: Lucia
authors: L
authors: Altucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004220:Disulfides / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D010091:Oximes; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; C571999:UVI5008