Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase
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Published:2023-12-02
Issue:12
Volume:16
Page:1681
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ISSN:1424-8247
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Container-title:Pharmaceuticals
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language:en
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Short-container-title:Pharmaceuticals
Author:
Alghareeb Sumiah A.1, Alsughayyir Jawaher1, Alfhili Mohammad A.1ORCID
Affiliation:
1. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
Abstract
Background: Hemolysis and eryptosis result in the premature elimination of circulating erythrocytes and thus contribute to chemotherapy-related anemia, which is extremely prevalent in cancer patients. Eriocitrin (ERN), a flavanone glycoside in citrus fruits, has shown great promise as an anticancer agent, but the potential toxicity of ERN to human erythrocytes remains unstudied. Methods: Erythrocytes were exposed to anticancer concentrations of ERN (10–100 μM) for 24 h at 37 °C, and hemolysis and associated markers were quantified using colorimetric assays. Eryptosis was assessed by flow cytometric analysis to detect phosphatidylserine (PS) exposure by annexin-V-FITC, intracellular Ca2+ using Fluo4/AM, and oxidative stress with 2-,7-dichlorodihydrofluorescin diacetate (H2DCFDA). ERN was also tested against specific signaling inhibitors and anti-hemolytic agents. Results: ERN caused significant, concentration-dependent hemolysis at 20–100 μM. ERN also significantly increased the percentage of eryptotic cells characterized by Ca2+ elevation and oxidative stress. Furthermore, the hemolytic activity of ERN was significantly ameliorated in the presence of D4476, NSC23766, isosmotic urea and sucrose, and polyethylene glycol 8000 (PEG). In whole blood, ERN significantly elevated MCV and ESR, with no appreciable effects on other peripheral blood cells. Conclusions: ERN promotes premature erythrocyte death through hemolysis and eryptosis characterized by PS externalization, Ca2+ accumulation, membrane blebbing, loss of cellular volume, and oxidative stress. These toxic effects, mediated through casein kinase 1α and Rac1 GTPase, can be ameliorated by urea, sucrose, and PEG. Altogether, these novel findings are relevant to the further development of ERN as an anticancer therapeutic.
Funder
Deputyship for Research and Innovation, Ministry of Education, Saudi Arabia
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference55 articles.
1. Klimek-Szczykutowicz, M., Szopa, A., and Ekiert, H. (2020). Citrus limon (Lemon) Phenomenon-A Review of the Chemistry, Pharmacological Properties, Applications in the Modern Pharmaceutical, Food, and Cosmetics Industries, and Biotechnological Studies. Plants, 9. 2. Maqsood, R., Khan, F., Ullah, S., Khan, A., Al-Jahdhami, H., Hussain, J., Weli, A.M., Maqsood, D., Rahman, S.M., and Hussain, A. (2023). Evaluation of Antiproliferative, Antimicrobial, Antioxidant, Antidiabetic and Phytochemical Analysis of Anogeissus dhofarica A. J. Scott. Antibiotics, 12. 3. Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health;Lv;Chem. Cent. J.,2015 4. Saini, R.K., Ranjit, A., Sharma, K., Prasad, P., Shang, X., Gowda, K.G.M., and Keum, Y.S. (2022). Bioactive Compounds of Citrus Fruits: A Review of Composition and Health Benefits of Carotenoids, Flavonoids, Limonoids, and Terpenes. Antioxidants, 11. 5. Gandhi, G.R., Vasconcelos, A.B.S., Wu, D.T., Li, H.B., Antony, P.J., Li, H., Geng, F., Gurgel, R.Q., Narain, N., and Gan, R.Y. (2020). Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies. Nutrients, 12.
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