Nobiletin and xanthohumol counteract the TNFα‐mediated activation of endothelial cells through the inhibition of the NF‐κB signaling pathway

Abstract

Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Given the ability of tumors to interfere with multiple or different molecular pathways to promote angiogenesis, there is an increasing need to therapeutically block tumor progression by targeting multiple antiangiogenic pathways. Natural polyphenols present health-protective properties, which are likely attributed to their ability to activate multiple pathways involved in inflammation, carcinogenesis, and angiogenesis. Recently, increased attention has been addressed to the ability of flavonoids, the most abundant polyphenols in the diet, to prevent cancer by suppressing angiogenesis. Here we investigate the mechanisms by which xanthohumol (the major prenylated flavonoid of the hop plant Humulus lupulus L.) and nobiletin (flavonoid from red-orange Citrus sinensis) can modulate the effects of Tumor Necrosis Factorα (TNF-α) on human umbilical vein endothelial cells (HUVEC). The results reported in this paper show that xanthohumol and nobiletin pretreatment of HUVEC inhibits the effects induced by TNF-α on cell migration, invasion capability, and colon cancer cell adhesion on the endothelial monolayer. Moreover, the pretreatment reduces metalloproteinases and adhesion molecules' expression. Finally, our results highlight that xanthohumol and nobiletin can counteract the effects of TNF-α on angiogenesis and invasiveness, mainly through Vascular Endothelial Growth Factor and NF-κB pathways. Since angiogenesis plays an important pathological role in the progression of several diseases, our findings may provide clues for developing xanthohumol and nobiletin as therapeutic agents against angiogenesis-associated diseases.

Effects of Flavonoids on Cancer, Cardiovascular and Neurodegenerative Diseases: Role of NF-κB Signaling Pathway

“…Xhantohumol and nobiletin, are the most abundant flavonoids extracted respectively from the hop plant and red-orange. Recently, authors showed the effects of these two compounds on colon cancer cells, demonstrating that they sensitize colorectal cancer stem cells to 5-fluorouracil (5-Fu) and oxaliplatin (FOX)-based chemotherapy and affect angiogenesis [26,27].…”

A Combination of Polymethoxyflavones from Citrus sinensis and Prenylflavonoids from Humulus lupulus Counteracts IL-1β-Induced Differentiated Caco-2 Cells Dysfunction via a Modulation of NF-κB/Nrf2 Activation

“…In the light of the strict interconnections between IBD, oxidative stress and inflammation and considering the anti-oxidative and anti-inflammatory properties of PMF and PF, we here investigated whether these polyphenols subclasses, alone or in combination, display protective effects in an in vitro model of IBD. To this aim, we used selected fractions of PMF (PMFF) and PF (PFF) isolated from the extracts of Citrus sinensis and Humulus lupulus respectively, either alone or in combination (MIX) as elsewhere reported [ 44 , 45 ]. Moreover, differentiated Caco-2 cells, an established model of the human intestinal barrier, were exposed to IL-1β either in the absence or in the presence of PMFF or PFF or MIX.…”