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Xem thêm: Regulation of WNT beta catenin pathway in the disease progression of osteosarcoma
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CHAPTER 1. Introduction
CHAPTER 2. Hypothesis and Aims
CHAPTER 3. Antitumor activity of natural small molecule compounds as Wnt/β-catenin antagonists against human osteosarcoma cells
As the activation of β-catenin/TCF transcriptional activity results from the accumulation of nuclear β-catenin [77], we subsequently examined whether curcumin or PKF118-310 treatments was associated with changes in the cellular contents and localizati...
(a)
(b)
Recent reports showed that the inhibition of the Wnt/(-catenin pathway by the dominant-negative form of the co-receptor, DN-LRP5, and the endogenous inhibitor, DKK-3, could result in a reduction of motility and invasiveness of osteosarcoma cells [51, ...
(a)
To confirm the contribution of Wnt/(-catenin activation in affecting osteosarcoma cell invasion, we next transfected U2OS cells with the wild-type β-catenin plasmid followed by curcumin treatment and performed similar Matrigel invasion assays. The pre...
Figure 3-10b, Wnt/β-catenin activation via the forced expression of wild-type (-catenin dramatically enhanced the invasion capacity of U2OS cells, but this effect could be effectively reversed by curcumin treatment in a dose-dependent manner. Specific...
CHAPTER 4. Functionalization of curcumin analogues as Wnt antagonists in osteosarcoma
Statistical significance for treatment groups were analyzed using the two-tailed Student’s t-test (SPSS, Chicago, IL). The difference between values for each treatment concentration and the respective controls was considered to be statistically signif...
The activation of β-catenin/TCF transcriptional activity results from the accumulation of nuclear β- catenin [77]. As we have previously shown that curcumin was capable of disrupting the translocation of β-catenin into the nucleus without changing the...
α-Tubulin
We have recently reported that activation of the Wnt/(-catenin pathway via forced expression of wild-type (-catenin plasmid drastically enhanced the invasive capacity of U2OS cells, but this effect was significantly reversed by curcumin in a dose-depe...
Based on the rationale of drug design as described in (Sections 4.2.2 and 4.2.3), we have synthesized and evaluated five series of curcumin analogues for improved potency as Wnt inhibitors in osteosarcoma. Our preliminary screening yielded 16 compound...
A study of SAR revealed that Series 3 (dibenzylidene-cyclohexanones) and Series 4 (dibenzylidene-cyclopentanones) analogues, both with conformationally restricted and bulkier tethers between the terminal phenyl rings, exhibited much higher Wnt inhibit...
To provide preliminary understanding of the interactions of curcumin analogues with various critical Wnt players, perturbations in gene levels of 84 Wnt signaling components and target genes by curcumin analogue 3-3 (the most potent analogue) were eva...
Our curcumin analogues were also found to be effective in reducing osteosarcoma cell invasiveness by between 34.8 - 71.0 % and 63.0 - 81.6 % at 1 µM and 5 µM respectively (Figure 4-3). The observed anti-invasive effects correlated with the down-regula...
Anomalous observation was made with regards to two genes, namely SFRP1 and NKD1. The down-regulation of mRNA SFRP1 level following treatment with analogue 3-3 is not unexpected since SFRP1 has been shown to be capable of increasing Wnt signaling in so...
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