Hit Identification and Functional Validation of Novel Dual Inhibitors of HDAC8 and Tubulin Identified by Combining Docking and Molecular Dynamics Simulations.

Chromatin organization, which is under the control of histone deacetylases (HDACs), is frequently deregulated in cancer cells. Amongst HDACs, HDAC8 plays an oncogenic role in different neoplasias by acting on both histone and non-histone substrates. Promising anti-cancer strategies have exploited dual-targeting drugs that inhibit both HDAC8 and tubulin.

The Mutyh base excision repair gene influences the inflammatory response in a mouse model of ulcerative colitis.

Background: The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress.

Overexpression of human NOX1 complex induces genome instability in mammalian cells.

The production of reactive oxygen species (ROS) in mammalian cells is tightly regulated because of their potential to damage macromolecules, including DNA. To investigate possible links between high ROS levels, oxidative DNA damage, and genomic instability in mammalian cells, we established a novel model of chronic oxidative stress by coexpressing the NADPH oxidase human (h) NOX1 gene together with its cofactors NOXO1 and NOXA1. Transfectants of mismatch repair (MMR)-proficient HeLa cells or MMR-defective Msh2(-/-) mouse embryo fibroblasts overexpressing the hNOX1 complex displayed increased intracellular ROS levels.

The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells.

Oxidation is a common form of DNA damage to which purines are particularly susceptible. We previously reported that oxidized dGTP is potentially an important source of DNA 8-oxodGMP in mammalian cells and that the incorporated lesions are removed by DNA mismatch repair (MMR). MMR deficiency is associated with a mutator phenotype and widespread microsatellite instability (MSI).