Triggering of Suicidal Erythrocyte Death Following Boswellic Acid Exposure

Cell Physiol Biochem. 2015;37(1):131-42. doi: 10.1159/000430339. Epub 2015 Aug 17.


Background/aims: The antinflammatory natural product boswellic acid is effective against cancer at least in part by inducing tumor cell apoptosis. Similar to apoptosis of nucleated cells erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca(2+)-activity ([Ca(2+)]i), energy depletion, ceramide formation and p38 kinase activation. The present study tested, whether and how boswellic acid induces eryptosis.

Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies, reactive oxygen species (ROS) from 2',7'-dichlorodihydrofuorescein diacetate (DCFDA) fluorescence, and cytosolic ATP concentration utilizing a luciferin-luciferase assay kit.

Results: A 24 hours exposure of human erythrocytes to boswellic acid (5 µg/ml) significantly increased the percentage of annexin-V-binding cells (to 9.3 ± 0.9 %) and significantly decreased forward scatter. Boswellic acid did not significantly modify [Ca(2+)]i, cytosolic ATP, ROS, or ceramide abundance. The effect of boswellic acid on annexin-V-binding was significantly blunted, but not abolished by p38 kinase inhibitors skepinone (2 µM) and SB203580 (2 µM).

Conclusions: Boswellic acid stimulates cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part dependent on p38 protein kinase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Annexin A5 / metabolism
  • Calcium / metabolism
  • Cell Death / drug effects*
  • Cell Size / drug effects
  • Ceramides / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Erythrocyte Membrane / drug effects
  • Erythrocyte Membrane / metabolism
  • Erythrocytes / drug effects*
  • Erythrocytes / metabolism
  • Hemoglobins / metabolism
  • Hemolysis / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Triterpenes / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Annexin A5
  • Ceramides
  • Hemoglobins
  • Imidazoles
  • Pyridines
  • Reactive Oxygen Species
  • Triterpenes
  • boswellic acid
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • Calcium