Sickle cell disease and β-thalassaemia are inherited haemoglobinopathies resulting in structural and quantitative changes in the β-globin chain. These changes lead to instability of the generated haemoglobin or to globin chain imbalance, which in turn impact the oxidative environment both intracellularly and extracellularly. The ensuing oxidative stress and the inability of the body to adequately overcome it are, to a large extent, responsible for the pathophysiology of these diseases. This article provides an overview of the main players and control mechanisms involved in the establishment of oxidative stress in these haemoglobinopathies.

Activating mutations in the RAS proto-oncogene result in constant stimulation of its downstream pathways, further leading to tumorigenesis. Transcription factor IID (TFIID) can be regulated by cellular signals to specifically alter transcription of particular subsets of genes. To investigate potential links between the regulation of TFIID function and the RAS-induced carcinogenesis, we monitored the expression of the TATA box-binding protein and its associated factors (TAF) in human colon carcinoma cells. We primarily identified TAF12 levels as being up-regulated in cell lines bearing natural RAS mutations or stably overexpressing a mutated RAS isoform via a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase -dependent pathway. We further showed by electrophoretic mobility shift assays and chromatin immunoprecipitation that the ETS1 protein was interacting with an ETS-binding site on the TAF12 promoter and was regulating TAF12 expression. The binding was enhanced in extracts from oncogenic RAS-transformed cells, pointing to a role in the RAS-mediated regulation of TAF12 expression. Reduction of TAF12 levels by small interfering RNA treatment induced a destabilization of the TFIID complex, enhanced E-cadherin mRNA and protein levels, and reduced migration and adhesion properties of RAS-transformed cells with epithelial to mesenchymal transition. Overall, our study indicates the importance of TAF12 in the process of RAS-induced transformation properties of human colon cells and epithelial to mesenchymal transition, most notably those related to increased motility, by regulating specifically expression of genes such as E-cadherin.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder, characterized, in most cases, by the presence of the Bcr-Abl fusion oncogene. Bcr-Abl is a constitutively active tyrosine kinase that is responsible for the malignant transformation. Targeting the Bcr-Abl kinase is an attractive treatment strategy for CML. First and second generation Bcr-Abl inhibitors have focused on targeting the ATP-binding domain of the kinase. Mutations in that region are relatively resistant to drug manipulation. Therefore, non-ATP-competitive agents have been recently developed and tested. In the present study, in an attempt to aid the design of new chemotypes with enhanced cytotoxicity against K562 cells, 3D pharmacophore models were generated and 3D-QSAR CoMFA and CoMSIA studies were carried out on the 33 novel Abl kinase inhibitors (E)-α-benzylthio chalcones synthesized by Reddy et al. A five-point pharmacophore with a hydrogen bond acceptor, two hydrophobic groups and two aromatic rings as pharmacophore features, and a statistically significant 3D-QSAR model with excellent predictive power were developed. The pharmacophore model was also used for alignment of the 33 compounds in a CoMFA/CoMSIA analysis. The contour maps of the fields of CoMFA and CoMSIA models were utilized to provide structural insight into how these molecules promote their toxicity. The possibility of using this model for the design of drugs for the treatment of β-thalassemia and sickle cell disease (SCD), since several Bcr-Abl inhibitors are able to promote erythroid differentiation and γ-globin expression in CML cell lines and primary erythroid cells is discussed.

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