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Anticancer Agents Med Chem. 2018;18(10):1432-1439. doi: 10.2174/1871520618666180209151750.

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

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Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Department of Human Science and Promotion of Quality of Life, the San Raffaele Open University of Rome, Rome, Italy.
Section of Animal Biology, Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy.
Department of Medical and Surgical Sciences and Advanced Technologies, Anatomic Pathology Section, School of Medicine, University of Catania, Catania, Italy.
Institute of Neurological Sciences, National Research Council, Catania, Italy.



Caffeine represents the most used psychoactive drug in the world acting through different mechanisms of action and on several molecular targets. 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. Moreover, we analyzed the activation of phosphoinositide three kinase (PI3K)/Akt and mammalian mitogen activated protein kinase/Erk kinase (MAPK/ERK) signaling cascades.


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.


The present data give new insight into antitumor activity of caffeine during GBM progression.


Caffeine; MAPK/ERK; PI3K/Akt; glioblastoma multiforme; hypoxia-inducible factors; vascular endothelium growth factor.

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