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

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

Abstract

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.

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

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Caffeine / chemistry
  • Caffeine / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Molecular Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factors / antagonists & inhibitors*
  • Vascular Endothelial Growth Factors / metabolism

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Protein Kinase Inhibitors
  • Vascular Endothelial Growth Factors
  • Caffeine