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Gallic Acid Triggers Iron-Dependent Cell Death with Apoptotic, Ferroptotic, and Necroptotic Features

Ho Man Tang1, Peter Chi Keung Cheung2

  • 1School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.

Toxins
|August 29, 2019
PubMed

Insights

Gallic acid (GA), a natural anti-cancer compound, triggers iron-dependent cell death pathways including apoptosis, ferroptosis, and necroptosis. This discovery offers new strategies to enhance GA

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Gallic acid (GA) is a natural compound found in various foods, recognized for its potential anti-cancer properties.
  • Previous research primarily linked GA's anti-cancer effects to the induction of apoptosis.
  • The precise mechanisms underlying GA's efficacy against cancer cells require further elucidation.

Purpose of the Study:

  • To investigate the novel cell death mechanisms induced by Gallic acid (GA) in cancer cells.
  • To determine if GA activates iron-dependent cell death pathways beyond apoptosis.
  • To explore strategies for enhancing the anti-cancer efficacy of GA.

Main Methods:

  • Time-lapse live-cell microscopy was employed to observe GA-induced cellular changes.
  • Apoptosis was assessed by monitoring mitochondrial cytochrome c release and caspase-3 activation.
  • Ferroptosis was identified by measuring lipid peroxidation, and necroptosis by assessing plasma membrane integrity.
  • The role of iron dependency was tested using the iron chelator deferoxamine.
  • The effect of a mixed lineage kinase domain-like protein (MLKL) inhibitor, necrosulfonamide, was evaluated for synergistic effects.

Main Results:

  • Gallic acid (GA) was found to induce a combination of apoptotic, ferroptotic, and necroptotic cell death.
  • The GA-induced cell death was confirmed to be iron-dependent, as it was completely inhibited by deferoxamine.
  • Co-treatment with necrosulfonamide, an MLKL inhibitor, synergistically enhanced cancer cell sensitivity to GA.
  • GA activates multiple cell death pathways simultaneously, highlighting a complex mechanism of action.

Conclusions:

  • Gallic acid (GA) triggers iron-dependent cell death through multiple pathways, including apoptosis, ferroptosis, and necroptosis.
  • The findings reveal new insights into the anti-cancer mechanisms of GA.
  • Targeting these specific cell death pathways or using agents like MLKL inhibitors could enhance GA's therapeutic potential in cancer treatment.
Keywords:
apoptosiscell deathdeferoxamineferroptosisgallic acidnecroptosisnecrosulfonamide

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