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Pharmacogenomics of Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Patrick Johnston, Howard L. McLeod
The most frequently used genome-wide approach in colorectal cancer is DNA microarray profiling. Maxwell et al. carried out a study to identify novel downstream mediators of tumor cell response to 5-FU. They found that 619 genes were upregulated greater than threefold by 5-FU. The genes that were consistently upregulated were spermine/speridine acetyl transfer-ase, which was involved in polyamine metabolism; annexin II, which was involved in DNA synthesis, cell proliferation, and apoptosis; thymosin β-10, which was a G actin binding protein involved in apoptosis; chaperonin 10, which was a heat shock protein involved in the folding of mitochondrial proteins; and MAT-8, which was a member of the FXYD family of proteins that regulate chloride ion transport. They further demonstrated that these genes were upregulated in response to both tomudex and oxaliplatin and furthermore that the basal levels of these genes were upregulated in a 5-FU-resistant colorectal cancer cell line compared to the parental line (159). Mariadason et al. carried out gene expression profiling on 30 colorectal cancer cell lines and correlated this with 5-FU sensitivity using three different assays of response. They were able to identify panels of genes that correlated with 5-FU sensitivity and further used leave-one-out cross-validation to demonstrate that these genes were predictive for 5-FU response. They noted that this gene set had a greater power to predict response than four “classical” determinants of 5-FU response: TS, TP, p53, and MMR status. Furthermore, they repeated the correlation analysis for sensitivity to CPT-11 and this generated a second gene set that showed great predictive power for sensitivity to CPT-11 (160). A second study then carried out gene expression profiling on 30 different colorectal cancer cell lines to select genes that could predict the apoptotic, response to oxaliplatin. Again the investigators used a leave-one-out cross-validation approach to determine this. They demonstrated that 80 genes best correlated with oxaliplatin-induced apoptosis, and that this gene set produced the most accurate prediction of oxaliplatin response (161).
Identification of cisplatin-binding sites on the large cytoplasmic loop of the Na+/K+-ATPase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jaroslava Šeflová, Petra Čechová, Tereza Štenclová, Marek Šebela, Martin Kubala
A functional NKA molecule is composed of two main subunits (denoted as α and β), which are often associated with a tissue-specific protein from FXYD family (Figure 1)8. The transmembrane domain of the catalytic α-subunit contains the binding sites for the transported cations and its large cytoplasmic part contains both ATP-binding and phosphorylation sites. Three large domains (named as A, P, and N) could be identified on the cytoplasmic side of the membrane (see Figure 1). The A-domain is formed by the N-terminus and loops between the transmembrane helices M2 and M3 (loop C23). The two other domains (N- and P-domain) are formed by a large cytoplasmic loop connecting the helices M4 and M5 (loop C45). The C45 loop plays a significant role in the NKA function as the nucleotide binding- and phosphorylation sites are localised within the N- and P-domain, respectively. The β-subunit has a single transmembrane helix and a large glycosylated ectodomain. It serves as a molecular chaperone assisting the correct α-subunit folding, and it probably also plays a role in the K+ countertransport or in the cell-cell adhesion processes9.
Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Marco T. C. Pessôa, Silmara L. G. Alves, Alex G. Taranto, José A. F. P. Villar, Gustavo Blanco, Leandro A. Barbosa
NKA is constituted by three different subunits: the α, β, and a smaller polypeptide, which depending on the tissue, consists of one of several members of the FXYD family of polypeptides4,5. The α subunit is responsible for the catalytic activity of NKA and contains the ATP, Na+, and K+ binding sites. The β subunit is a glycosylated polypeptide responsible for the folding and functional competence of the NKA α subunit. The FXYD peptide functions as a modulator of the catalytic properties of NKA. Four isoforms of the NKA α subunit and three NKA β isoforms have been identified in mammals (α1, α2, α3, α4, β1, β2, and β3). This molecular heterogeneity, in addition to various assemblies of the α and β subunits, provides cells with the versatility of adjusting Na+ and K+ gradients to the needs of each cell type5.