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The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis.

Authors :
Ghashghaeinia M
Koralkova P
Giustarini D
Mojzikova R
Fehrenbacher B
Dreischer P
Schaller M
Mrowietz U
Martínez-Ruiz A
Wieder T
Divoky V
Rossi R
Lang F
Köberle M
Source :
Apoptosis : an international journal on programmed cell death [Apoptosis] 2020 Oct; Vol. 25 (9-10), pp. 674-685.
Publication Year :
2020

Abstract

Costunolide, a natural sesquiterpene lactone, has multiple pharmacological activities such as neuroprotection or induction of apoptosis and eryptosis. However, the effects of costunolide on pro-survival factors and enzymes in human erythrocytes, e.g. glutathione and glucose-6-phosphate dehydrogenase (G6PDH) respectively, have not been studied yet. Our aim was to determine the mechanisms underlying costunolide-induced eryptosis and to reverse this process. Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry, and intracellular glutathione [GSH] <subscript>i</subscript> from high performance liquid chromatography. The oxidized status of intracellular glutathione and enzyme activities were measured by spectrophotometry. Treatment of erythrocytes with costunolide dose-dependently enhanced the percentage of annexin-V-binding cells, decreased the cell volume, depleted [GSH] <subscript>i</subscript> and completely inhibited G6PDH activity. The effects of costunolide on annexin-V-binding and cell volume were significantly reversed by pre-treatment of erythrocytes with the specific PKC-α inhibitor chelerythrine. The latter, however, had no effect on costunolide-induced GSH depletion. Costunolide induces eryptosis, depletes [GSH] <subscript>i</subscript> and inactivates G6PDH activity. Furthermore, our study reveals an inhibitory effect of chelerythrine on costunolide-induced eryptosis, indicating a relationship between costunolide and PKC-α. In addition, chelerythrine acts independently of the GSH depletion. Understanding the mechanisms of G6PDH inhibition accompanied by GSH depletion should be useful for development of anti-malarial therapeutic strategies or for synthetic lethality-based approaches to escalate oxidative stress in cancer cells for their sensitization to chemotherapy and radiotherapy.

Details

Language :
English
ISSN :
1573-675X
Volume :
25
Issue :
9-10
Database :
MEDLINE
Journal :
Apoptosis : an international journal on programmed cell death
Publication Type :
Academic Journal
Accession number :
32638182
Full Text :
https://doi.org/10.1007/s10495-020-01620-6