Olaparib for the treatment of the BRCA1 or BRCA2 gene mutations in cancer

A broad range of pathological disorders is linked to oxidative stress, including carcinogenesis and several age-dependent disorders . Oxidative stress is defined as an imbalance Olaparib in which the production of reactive oxygen species overcomes the antioxidative cell defence system. Oxidative stress can be induced by exogenous and endogenous sources. For instance, hydrogen peroxide and chemotherapeutic reagents are exogenous sources of ROS, whereas mitochondrial energymetabolism is considered a major source for the production of ROS within the cell . ROS can directly react with macromolecules, such as DNA, lipids, and proteins. Oxidative DNA lesions, if unrepaired, can induce mutations and deletions in both nuclear and mitochondrial genomes and chromosomal abnormalities. Cells are also very sensitive to lipid Panobinostat peroxidation and most amino acid residues in a protein can be oxidized by ROS. Often these modifications impair protein function . Antioxidant defences are built in a complex network of nonenzymatic and enzymatic components of the cell.
This network has been extensively reviewed . In short, Glutathione is a nonenzymatic antioxidant, which acts in the cellular thiol/disulfide system, with the ratio of GSH to GSSH mirroring the redox status of the cell. On the other hand, enzymatic antioxidants include superoxide dismutases SODs, OSI-906 catalase, peroxiredoxins , and glutathione peroxidases . The toxicity of ROS is only one facet of their action. ROS are also produced at low level within the cell, where they can play an important role in the redox-dependent regulation of signaling . Hence, ROS are implicated in several cellular processes, including cell proliferation, cell cycle arrest, and programmed cell death . Cellular responses to DNA damage or oxidative stress are critical for survival, and the direct link between ROS and oxidative DNA damage indicates the interplay of ROS signaling with the DNA damage response .
Evidence indicates the involvement of the phosphatidylinositol-3-kinases- related kinases, Ataxia telangiectasia mutated , DNAdependent protein kinase catalytic subunit , and ATM- and Rad-3 related in oxidative DNA lesion repair and signaling response . This finding together with the emerging role of c-Abl in the DDR and in oxidative DNA damage seems to point out a role for these DDR kinases as “sensors” for redox signaling. In particular, herein we discuss how an aberrant c-Abl signaling may contribute to maintain high levels of ROS that in turn can damage organelles, mitochondria, and DNA, with these effects ending towards neuronal Paclitaxel degeneration. Oxidative stress contributes to the pathogenesis of a large number of human disorders. No doubt that a better understanding of the controlled production of ROS should provide the rationale for novel therapeutic treatments . ROS signaling is reversible, tightly controlled through a regulatory network.
This network results from a concerted assembly of protein complexes, built through protein interactions mediated by interaction modules and posttranslational modifications in the binding partners. Protein modularity and the reversible nature of posttranslational modifications allow the dynamic assembly of local temporary signaling circuits regulated by feedback controls. The strength and the duration of redox signaling are regulated via the oxidative modifications of the kinases and phosphatases that in turn control the activity of enzymes involved in antioxidant activities and vice versa. Oxidant level modulates c-Abl activity . In turn, c-Abl can interact with several enzymes implicated in controlling the redox state of the cell. One of them, the catalase is an immediate effector of the PCI-34051 antioxidant cellular defense by converting H2O2 to H2O and O2 in the peroxisomes. c-Abl and the product of the c-Abl-related gene target catalase on the two residues Y321 and Y386 leading to its ubiquitination and to a consequent proteasomaldepend- ent degradation of the enzyme .
Similarly, c- Abl-deficient cells display a higher level of expression of the antioxidant protein peroxiredoxin I . Prx1 is considered a physiological inhibitor of c-Abl. Prx1 interacts with the SH3 domain of c-Abl and inhibits its catalytic activity . Depending on the oxidative level in the cell, glutathione peroxidase1 can be phosphorylated on Tyr-96 and activated by c-Abl/Arg . In short, c-Abl activation has mostly a negative effect on enzymes involved in the antioxidant defence, with rare exceptions.

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S1060 Olaparib (AZD2281) Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations. (863) (18)

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