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 apoptosisinducing 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. Ó2011 AACR.

Pathway of 3-MCPD-induced apoptosis in human embryonic kidney cells

“…Because of this, the cell is subject to strict (self) control and is eliminated without affecting neighboring cells (Chopra et al, 2010). Three main components are involved in apoptosis signal transduction: mitochondrial pathway (Zhang et al, 2010), death receptor pathway (Nebbioso et al, 2011) and endoplasmic reticulum pathway (Zhang and Kaufman, 2008). All pro-apoptotic molecules exist in intact cells and do not have to be synthesized newly (Ashkenazi, 2008).…”

Epigenetic modulator UVI5008 inhibits MRSA by interfering with bacterial gyrase

“…Valproic acid (VPA), 2-4-pyridinedicarboxylic acid (2–4 Pyr), GSK-126, ellagic acid, and UVI5008 demonstrated antimicrobial activity. UVI5008 is an epigenetic modulator, while the remaining compounds have anticancer and/or cell-differentiating properties 23–26 . UVI5008 was selected for its high potency as an antimicrobial and its potentially novel mechanism of action.

Figure 1Radar graph representation of the effect of epigenetic compounds on two Gram-negative ( E .

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Molecular Pathways: The Complexity of the Epigenome in Cancer and Recent Clinical Advances

“…Although mutated targets might benefit from a selective epi-drug approach (better if active exclusively on the mutant), a broad modulator might present greater advantages in the case of concomitant alterations of different chromatin modifiers and marks. Multiple epi-modulators (targeting more than one class of enzymes, for instance) may also represent a promising approach (68), as could the creation of hybrid molecules able to act broadly on a class of epi-modifiers and to simultaneously mark a specific non-epi-target within cancer cells. This last approach, which still needs to be fully validated, might "remodulate" chromatin in a more targeted manner.…”