Inhibition of Erythrocyte Cell Membrane Scrambling Following Energy Depletion and Hyperosmotic Shock by Alectinib.

Abstract

BACKGROUND/AIMS:

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is clinically used for the treatment of ALK positive non-small-cell lung cancer. At least in part the substance is effective by triggering suicidal death or apoptosis of tumor cells. Erythrocytes are lacking mitochondria and nuclei, key organelles of apoptosis but are, similar to apoptosis of nucleated cells, able to enter suicidal erythrocyte death or eryptosis. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress, and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether alectinib influences eryptosis.

METHODS:

Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding and cell volume from forward scatter. Measurements were made without or with energy depletion (glucose deprivation for 48 hours), hyperosmotic shock (+550mM sucrose for 6 hours), oxidative stress (50 min exposure to 0.3 mM tert-butylhydroperoxide), and Ca2+ loading (60 minutes treatment with 1 µM Ca2+ ionophore ionomycin).

RESULTS:

A 48 hours exposure of human erythrocytes to alectinib (150-600 ng/ml) did not significantly modify the percentage of annexin-V-binding cells and forward scatter. Energy depletion, hyperosmotic shock, oxidative stress and Ca2+ loading were each followed by profound and significant increase of the percentage annexin-V-binding erythrocytes and a significant decrease of forward scatter. The effects of energy depletion and hyperosmotic shock, but not of oxidative stress or Ca2+ loading on annexin-V-binding were significantly blunted in the presence of alectinib (150-600 ng/ml). In none of the conditions was forward scatter significantly modified by alectinib.

CONCLUSION:

Alectinib inhibits cell membrane scrambling following energy depletion and hyperosmotic shock.

• Authors: Abdulla Al Mamun Bhuyan, Florian Lang
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 51 Issue 5 Pg. 1996-2009 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30522123 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Carbazoles
• Phosphatidylserines
• Piperidines
• Protein Kinase Inhibitors
• alectinib

Topics

• Carbazoles (pharmacology)
• Energy Metabolism (drug effects)
• Eryptosis (drug effects)
• Erythrocyte Membrane (drug effects, metabolism)
• Erythrocytes (cytology, drug effects, metabolism)
• Humans
• Osmotic Pressure (drug effects)
• Oxidative Stress (drug effects)
• Phosphatidylserines (analysis, metabolism)
• Piperidines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)