Document Detail

Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR-mediated leukemia cell death.
MedLine Citation:
PMID:  22428532     Owner:  NLM     Status:  MEDLINE    
4-(Hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid with a strong apoptotic effect towards different cancer cell lines in vitro, and it is currently tested in clinical trials. Increases of reactive oxygen species (ROS) and modulation of endogenous sphingolipid levels are well-described events observed upon 4-HPR treatment, but there is still a lack of understanding of their relationship and their contribution to cell death. LC-MS analysis of sphingolipids revealed that in human leukemia CCRF-CEM and Jurkat cells, 4-HPR induced dihydroceramide but not ceramide accumulation even at sublethal concentrations. Myriocin prevented the 4-HPR-induced dihydroceramide accumulation, but it did not prevent the loss of viability and increase of intracellular ROS production. On the other hand, ascorbic acid, Trolox, and vitamin E reversed 4-HPR effects on cell death but not dihydroceramide accumulation. NDGA, described as a lipoxygenase inhibitor, exerted a significantly higher antioxidant activity than vitamin E and abrogated 4-HPR-mediated ROS. It did not however rescue cellular viability. Taken together, this study demonstrates that early changes observed upon 4-HPR treatment, i.e., sphingolipid modulation and ROS production, are mechanistically independent events. Furthermore, the results indicate that 4-HPR-driven cell death may occur even in the absence of dihydroceramide or ROS accumulation. These observations should be taken into account for an improved design of drug combinations.
Aintzane Apraiz; Jolanta Idkowiak-Baldys; Naiara Nieto-Rementería; María Dolores Boyano; Yusuf A Hannun; Aintzane Asumendi
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-19
Journal Detail:
Title:  Biochemistry and cell biology = Biochimie et biologie cellulaire     Volume:  90     ISSN:  1208-6002     ISO Abbreviation:  Biochem. Cell Biol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-30     Completed Date:  2012-07-16     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8606068     Medline TA:  Biochem Cell Biol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  209-23     Citation Subset:  IM    
Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Sarriena s/n, 48940 Leioa (Bizkaia), Spain.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Antioxidants / pharmacology
Apoptosis / drug effects*
Ascorbic Acid / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Ceramides / metabolism*
Fenretinide / pharmacology*
Flavanones / pharmacology
Lipid Peroxidation
Lipoxygenase Inhibitors / pharmacology
Mitochondria / metabolism
Nordihydroguaiaretic Acid / pharmacology
Oxidative Stress
Oxidoreductases / metabolism
Reactive Oxygen Species / metabolism*
Sphingolipids / biosynthesis
Vitamin E / pharmacology
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antioxidants; 0/Ceramides; 0/Flavanones; 0/Lipoxygenase Inhibitors; 0/Reactive Oxygen Species; 0/Sphingolipids; 0/dihydroceramide; 1406-18-4/Vitamin E; 49QAH60606/baicalein; 50-81-7/Ascorbic Acid; 500-38-9/Nordihydroguaiaretic Acid; 65646-68-6/Fenretinide; EC 1.-/Oxidoreductases; EC 1.3.1.-/dihydroceramide desaturase

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