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  • However from our meta analysis emerge

    2024-04-02

    However, from our meta-analysis emerge some strategic considerations for the continued use of antiangiogenic drugs for glioblastoma patients:
    Conflict of interest
    Funding
    Introduction Angiogenesis is a physiological process involving the formation of new blood vessels from pre-existing blood vessels. It is a complex process characterized by the proliferation, migration, sprouting and elongation of endothelial ldk378 [1], and plays an important role during cell reproduction and organ development, as well as in wound healing processes. Under pathological conditions, angiogenesis is poorly regulated and contributes to the pathogenesis of various diseases such as rheumatoid arthritis, inflammation, psoriasis, degenerative eye conditions and, of particular relevance to our study, cancer [2]. Sustained angiogenesis is one of the central hallmarks of cancer [3], [4] and has been validated as a key target for cancer therapy [5], as evidenced by several antiangiogenic agents having entered clinical practice in the last decade (for example, bevacizumab (Avastin® for several metastatic cancers) and sunitinib maleate (SU11248, Sutent® for renal cell carcinoma and gastrointestinal stromal tumour)). Flavonoids are polyphenolic compounds that have attracted ongoing and recent interest due to their potential anticancer properties. They are very well known for their antiproliferative activities against various cell lines [6] with some flavonoids such as flavopiridol [7], ldk378 [8], [9], silibinin (also known as silybin) [10], quercetin [11] and its derivative QC12 [12] having progressed to various stages of clinical trials. Interestingly, recent studies have highlighted that two common dietary flavonoids (quercetin and luteolin) inhibit angiogenesis in vitro and in vivo[13], [14] at concentrations 10–40 μM. Also, other structurally similar flavones have been reported to possess antiangiogenic properties. In order to develop and optimise the flavone scaffolds into a pharmaceutical agent, a better understanding of the structure-activity relationships (SARs) is crucial. Hence, in this study, the antiangiogenic properties of a panel of small molecules, comprised of quercetin and luteolin, as well as their rationally designed and synthesised derivatives, are probed to allow a better understanding of the structure activity relationships of flavonoids as antiangiogenic agents. Many antiangiogenic agents exhibit their action by interfering with the vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR2) [15]. Therefore, the compounds reported in our study were evaluated for their potential to inhibit the VEGF-stimulated effects in an in vitro model comprised of endothelial cells. The molecular mechanism of action of these derivatives was investigated using Western blotting and additionally in silico studies were conducted to probe the interactions of this panel of molecules with VEGFR2 and VEGF. Additionally, we probed the interactions of these synthesised compounds with a model lipid bilayer in order to determine the possible contribution of a membrane perturbation effect towards the observed biological activity. Finally, as flavonoid derivatives are known to display direct anticancer activity against tumour cells, cytotoxicity studies against a breast cancer cell line (MCF-7) and a chemotherapy resistant sub-strain (MCF-7/DX) were also carried out. This cytotoxicity assessment was carried out to investigate how variations in the chemical structure of the flavonoid derivatives affected their activity, but also to establish the concentrations required to elicit direct anticancer activity compared to those required for antiangiogenic effects. Indeed, a widely reported problem associated with antiangiogenic drugs that target endothelial proliferation is their inhibition of the proliferation of other cell types, which leads to undesirable cell toxicity; molecules with high selectivity towards VEGF/VEGFR2 with low cytotoxicity are considered to be ideal candidates for antiangiogenic therapy as well as for combination therapy [16].