Background: 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.
Methods: 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.
Results: 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.
Conclusion: The present data give new insight into antitumor activity of caffeine during GBM progression.