Back to Search
Start Over
The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis.
- 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.
- Subjects :
- Apoptosis drug effects
Calcium metabolism
Eryptosis drug effects
Erythrocytes drug effects
Erythrocytes pathology
Glucosephosphate Dehydrogenase antagonists & inhibitors
Glutathione genetics
Humans
Oxidative Stress drug effects
Protein Kinase C-alpha antagonists & inhibitors
Reactive Oxygen Species
Sesquiterpenes pharmacology
Benzophenanthridines pharmacology
Enzyme Inhibitors pharmacology
Eryptosis genetics
Glucosephosphate Dehydrogenase genetics
Protein Kinase C-alpha genetics
Subjects
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