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Xenobiotica
the fate of foreign compounds in biological systems
Volume 53, 2023 - Issue 5
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Molecular Toxicology

Metabolic exhaustion and casein kinase 1α drive deguelin-induced premature red blood cell death

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Pages 445-453 | Received 20 Jul 2023, Accepted 11 Aug 2023, Published online: 21 Aug 2023
 

Abstract

1. Deguelin (DGN), a retinoid isolated from many plants, exhibits a potent anticancer activity against a wide spectrum of tumour cells. There is a dearth of evidence, however, regarding the toxicity of DGN to red blood cells (RBCs). This is relevant given the prevalent chemotherapy-associated anaemia observed in cancer patients.

2. RBCs were exposed to 1-100 μM of DGN for 24 h at 37 °C. Haemolysis and related markers were photometrically measured while flow cytometry was employed to detect phosphatidylserine exposure through Annexin-V-FITC binding and light scatter properties. Additionally, cytosolic Ca2+ and reactive oxygen species were quantified using Fluo4/AM and H2DCFDA, respectively. DGN was also tested against specific signalling inhibitors in addition to vitamin C and ATP.

3. DGN caused a significant increase in Annexin-V-positive cells which was accompanied by cell shrinkage without Ca2+ elevation or oxidative stress. DGN also elicited dose-responsive haemolysis which was ameliorated by preventing KCl efflux and in the presence of sucrose, D4476, and ATP. In whole blood, DGN significantly reduced the reticulocyte count and increased platelet distribution width and large cell count.

4. DGN triggers premature RBC eryptosis and haemolysis through casein kinase 1α and ATP depletion, and exhibits a specific toxicity towards reticulocytes and platelets.

Disclosure statement

The authors report no declaration of interests.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, M.A.A., upon reasonable request.

Additional information

Funding

This work was funded by the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia under grant number IFKSUOR3-015-1.

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