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The current study describes the development of in silico models based on a novel alternative of the MTD-PLS methodology (Partial-Least-Squares variant of Minimal Topologic Difference) developed by our group to predict the inhibition of GSK-3β by indirubin derivatives. The new MTD-PLS methodology involves selection rules for the PLS equation coefficients based on physico-chemical considerations aimed at reducing the bias in the output information. These QSAR models have been derived using calculated fragmental descriptors relevant to binding including polarizability, hydrophobicity, hydrogen bond donor, hydrogen bond acceptor, volume and electronic effects. The MTD-PLS methodology afforded moderate but robust statistical characteristics (R2 Y(CUM) = 0.707, Q2(CUM) = 0.664). The MTD-PLS model obtained has been validated in terms of predictive ability by joined internal-external cross-validation applying Golbraikh-Tropsha criteria and Y-randomization test. The information supplied by the MTD-PLS model has been evaluated against Fujita-Ban outcomes that afforded a statistically reliable model (R2=0.923). Furthermore, the results originated from QSAR models were laterally validated with docking insights that suggested the substitution pattern for the design of new indirubins with improved pharmacological potential against GSK-3β. The new restriction rules introduced in this paper are applicable and provide reliable results in accordance with physico-chemical reality.
Selenium compounds have been implicated as anticancer agents; however, the mechanism of their inhibitory action against cancer development has not been extensively investigated. A constitutive activation of the Wnt/β-catenin pathway is a central event in colorectal carcinogenesis. In this pathway, excessive cell proliferation is initiated by generation of β-catenin followed by overexpression of proto-oncogenes, such as c-Myc. It is believed that under physiological conditions the level of c-Myc is efficiently controlled by accessibility of the β-catenin protein through the process of phosphorylation by glycogen synthase kinase 3β (GSK-3β). Here, we determined whether selenomethionine (SeMet) can inhibit cell growth and affect the Wnt/β-catenin pathway in the HT-29 human colorectal cancer cells in vitro. The effective cytotoxic doses of SeMet have been selected after 48 h of incubation of this compound with colorectal cancer HT-29 cell line. MTT assay was used to assess cell viability and the protein and mRNA levels of β-catenin and c-Myc were determined by Western blotting and qPCR, respectively. SeMet potently inhibited growth of HT-29 cells, significantly decreased level of the β-catenin protein and mRNA concentration, down-regulated the c-Myc gene expression and up-regulated the pro-apoptotic Bax protein level. Moreover, SeMet increased the level of GSK-3β phosphorylated at serine 9 (S9) and significantly increased the level of β-catenin phosphorylated at S33 and S37. We conclude that SeMet suppresses growth of HT-29 colorectal cancer cells by a mechanism linked to the Wnt/β-catenin pathway, however, degradation of β-catenin may occur independently of GSK-3β catalytic activity and its phosphorylation status.
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