Caffeine Effect on HIFs/VEGF Pathway in Human Glioblastoma Cells Exposed to Hypoxia

Abstract

Caffeine represents the most used psychoactive drug in the world acting as a non-selective adenosine receptor antagonist. It exerts an anti-cancer role in glioblastoma multiforme (GBM). This neoplasia is characterized by extensive hypoxic foci triggering hypoxia-inducible factors (HIFs) expression. Among these factors, HIF-1α performs a crucial role in the induction of vascular endothelium growth factor (VEGF), a key player in angiogenesis and cell migration. In this work, we have investigated whether caffeine counteracts GBM progression by modulating hypoxic event. Our results have indicated that this psychostimulant drug significantly reduced HIF-1α and VEGF expression in GBM cells exposed to hypoxia. This effect is mediated through inhibition of PI3K/Akt and MAPK/ERK signaling pathways both implied in HIFs regulation.

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

“…In addition, caffeine reduces the levels of expression of VEGF, one of the most relevant growth factors involved in angiogenic signaling, in the chick embryo chorioallantoic membrane [ 17 , 18 ] and in zebrafish larvae [ 19 ]. These data are consistent with the observation that caffeine inhibits VEGF expression in tumor cells via an adenosine receptor antagonist mechanism of action [ 20 , 21 ]. In addition, in keeping with a direct effect on endothelial cells, caffeine induces apoptosis in human umbilical vein endothelial cells (HUVECs) [ 17 ].…”

“…Methylxanthines, including caffeine, are known to act via adenosine receptor antagonism and phosphodiesterase inhibition [ 14 , 15 ], and both actions have been implicated in the antiangiogenic pathways. It has been shown that caffeine inhibits growth factors involved in angiogenesis in different cellular models [ 16 , 17 , 20 ]. In addition, evidence is available showing that other methylxanthines, such as pentoxifylline [ 27 ] and theophylline [ 28 ], possess antiangiogenic properties.…”

Coffee and tea consumption and the risk of glioma: a systematic review and dose–response meta-analysis

“…6 Depending on the experimental condition, caffeine may facilitate and limit the development of malignant cells by reducing cerebral blood flow and eventually restricting access to oxygen and nutrients, thereby inhibiting angiogenesis and carcinogenesis. 6,[34][35][36] With regards to glioblastoma, caffeine has been reported to decelerate the growth and invasion of glioblastoma and consequently prolong survival by inhibiting calcium release channel, 37 reducing hypoxia-inducible factors (HIFs)-1α and vascular endothelium growth factor (VEGF) expression in glioblastoma cells, 38 reducing the invasion of glioma cells from different signalling pathways, 39,40 and promoting FoxO1-Bim mediated cell apoptosis. 41 One of the limitations encountered in this study is that we are unable to provide subset analysis on types of coffee and teas, and other specifics such as filtered or decaffeinated coffee; because most of studies did not report it.…”

Antitumor effects of the silencing of programmed cell death ligand�1 in colorectal cancer via immunoregulation

“…Activation of PI3K can regulate the growth of tumor cells and prevent apoptosis ( 28 ) by activating a variety of downstream signals, including AKT, also known as PKB (protein kinase B), a serine/threonine kinase ( 13 ). AKT plays a key role in protein synthesis, cell metabolism, cell growth and proliferation, and angiogenesis ( 29 , 30 ). It has previously been demonstrated that PI3K/AKT signaling pathway can affect cell apoptosis through a variety of mechanisms, including promoting P53 nucleus translocation ( 28 , 31 ).…”