American Association for Cancer Research
15357163mct110525-sup-s3_pdf_46k.pdf (46.14 kB)

Supplementary Figure 3 from Death Receptor Pathway Activation and Increase of ROS Production by the Triple Epigenetic Inhibitor UVI5008

Download (46.14 kB)
journal contribution
posted on 2023-04-03, 13:25 authored by Angela Nebbioso, Raquel Pereira, Harshal Khanwalkar, Filomena Matarese, José García-Rodríguez, Marco Miceli, Colin Logie, Valerie Kedinger, Felicetto Ferrara, Hendrik G. Stunnenberg, Angel R. de Lera, Hinrich Gronemeyer, Lucia Altucci

PDF file - 46K



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. Mol Cancer Ther; 10(12); 2394–404. ©2011 AACR.