Biochimie
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Blocking αvβ3 integrin by a recombinant RGD disintegrin impairs VEGF signaling in endothelial cells.
Vascular endothelial growth factor (VEGF) and αvβ3 integrin are key molecules that actively participate in tumor angiogenesis and metastasis. Some integrin-blocking molecules are currently under clinical trials for cancer and metastasis treatment. However, the mechanism of action of such inhibitors is not completely understood. ⋯ DisBa-01 does not affect the release of VEGF by fibroblasts or breast cancer cells but it strongly decreases the expression of VEGF mRNA and of its receptors, vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) in endothelial cells. DisBa-01 at nanomolar concentrations also modulates metalloprotease 2 (MMP-2) and 9 (MMP-9) activity, the latter being decreased in fibroblasts and increased in MDA-MB-231 cells. In conclusion, these results demonstrate that αvβ3 integrin inhibitors may induce distinct effects in the cells of the tumor microenvironment, resulting in blockade of angiogenesis by impairing of VEGF signaling and in inhibition of tumor cell motility.
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The transcription factor hypoxia-inducible factor-1 (HIF-1) is an important regulator of the tumor response to hypoxia, including increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. In the current study, small interfering RNA (siRNA)-mediated knockdown of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) suppressed hypoxia-induced stimulation of HIF-1α protein expression in PC3 human prostate cancer cells. ⋯ Inactivation of the phosphoinsotide-3 kinase (PI3K)/Akt pathway decreased HIF-1α expression through inactivation of Sp1. Thus, IDPm siRNA functioned as a potentially useful agent for targeting chemo- and radio-resistant hypoxic cells within solid tumors through inhibition of HIF-1α expression.
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The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes. AEA is inactivated by fatty acid amide hydrolase (FAAH), that is inhibited competitively by hydroxyanandamides (HAEAs) generated from AEA by lipoxygenase activity. Among these derivatives, 15-HAEA has been shown to be an effective (K(i) approximately 0.6 muM) FAAH inhibitor, that blocks also type-1 cannabinoid receptor (CB1R) but not other components of the "endocannabinoid system (ECS)", like the AEA transporter (AMT) or CB2R. ⋯ We show that 15-MeOAEA, unlike 15-AcOAEA, is still a powerful competitive inhibitor of FAAH (K(i) approximately 0.7 muM), and that both derivatives have negligible interactions with the other proteins of ECS. Therefore, 15-MeOAEA is a FAAH inhibitor more selective than 15-HAEA. Further molecular dynamics analysis gave clues to the molecular requirements for the interaction of 15-HAEA and 15-MeOAEA with FAAH.
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The n-6 fatty acid arachidonic acid (AA; 20:4n-6) gives rise to eicosanoid mediators that have established roles in inflammation and AA metabolism is a long recognised target for commonly used anti-inflammatory therapies. It has generally been assumed that all AA-derived eicosanoids are pro-inflammatory. However this is an over-simplification since some actions of eicosanoids are anti-inflammatory (e.g. prostaglandin (PG) E(2) inhibits production of some inflammatory cytokines) and it has been discovered quite recently that PGE(2) inhibits production of inflammatory leukotrienes and induces production of inflammation resolving lipoxin A(4). ⋯ In addition to modifying the profile of lipid-derived mediators, fatty acids can also influence peptide mediator (i.e. cytokine) production. To a certain extent this action may be due to the altered profile of regulatory eicosanoids, but it seems likely that eicosanoid-independent actions are a more important mechanism. Indeed effects on transcription factors that regulate inflammatory gene expression (e.g. nuclear factor kappaB) seem to be important.
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Oral administration of bovine lactoferrin (bLF) inhibits carcinogenesis in the colon and other organs in rats, and lung metastasis in mice. A likely mechanism by which bLF mediates its anticarcinogenesis effects is by enhanced expression of cytokines and subsequent activation of immune cells. Oral administration of bLF enhances expression of interleukin-18 (IL-18) mRNA in the mucosa of the small intestine of mice. ⋯ Thus, bLF activates an effector pathway mediated by IFNgamma, caspase-1, and IL-18. We also show that ingested bLF is able to activate more than a single effector pathway. For example, in GKO mice while bLF administration could not activate the IFNgamma/caspase-1/IL-18 effector pathway, it was able to inhibit tumor growth and metastasis by activation of an IFNalpha/IL-7 effector pathway.