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.
Highlights
Cancer is a multistep process involving acquisition of unlimited replicative potential, self-sustained growth with loss of sensitivity toward apoptogenic and checkpoint controls [1]
UVI5008 induced cell death (Fig. 1B) and apoptosis by activation of both initiator, executor caspases (Fig. 1C), and loss of mitochondrial membrane potential in cancer cells derived from leukemias (U937, Ku-812F, and K562) or solid tumors, such as breast (MCF7), osteosarcoma (U2OS), prostate (DU145), colon www.aacrjournals.org
In addition to the increase of histone H3 acetylation expected for an HDAC inhibitors (HDACi), we identified a histone H3–derived peptide that is acetylated at K56 (Supplementary Fig. S2C and Table S1)
Summary
Cancer is a multistep process involving acquisition of unlimited replicative potential, self-sustained growth with loss of sensitivity toward apoptogenic and checkpoint controls [1]. These aberrations are caused by a series. Authors' Affiliations: 1Dipartimento di Patologia generale, Seconda Universita di Napoli, Vico L. de Crecchio 7; 2CNR-IGB, Via P. Castellino; 3Ospedale Cardarelli, Napoli, Italy; 4Departamento de Química Organica, Facultade de Química, Universidade de Vigo, Vigo, Spain; 5Department of Cancer Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch Cedex, Strasbourg, France; and 6NCMLS, Department of Molecular Biology, Radboud University, GA Nijmegen, the Netherlands.
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