Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea towards erythroid differentiation.
Resveratrol, a natural dietary polyphenol, has been postulated to be implicated in the cardioprotective effect of red wine and the low incidence of breast and prostate cancers among vegetarians and Orientals respectively. This compound inhibits ribonucleotide reductase as does hydroxyurea, the first therapeutic agent used in the treatment of sickle cell disease. Using the human erythroleukaemic K562 cell line as an in vitro model, we show here that 50 micromol/l of resveratrol induced a higher haemoglobin production (sevenfold) in K562 cells than 500 micromol/l of hydroxyurea (3.5-fold). This erythroid differentiation was linked to a dose- and time-dependent inhibition of cell proliferation associated with an equivalent increased expression of p21 mRNA, but with a higher increased level of p21 protein (sixfold) for cells treated with resveratrol than for those treated with hydroxyurea (1.5-fold). We also show that 50 micromol/l of resveratrol and 25 micromol/l of hydroxyurea induced variable but similar enhancements of fetal haemoglobin synthesis in cultured erythroid progenitors for the majority of the sickle cell patients studied. These inductions were linked to, but not correlated with, a variable decrease in erythroid burst-forming unit clone number. Taken together, these results show that resveratrol merits further investigations in sickle cell disease therapy.
Rodrigue
C M
CM
INSERM U474, Maternité Port-Royal, ICGM Cochin, Paris, France.
Arous
N
N
Bachir
D
D
Smith-Ravin
J
J
Romeo
P H
PH
Galacteros
F
F
Garel
M C
MC
D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy*; D008954:Models, Biological; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D013267:Stilbenes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005319:Fetal Hemoglobin; D012264:Ribonucleotide Reductases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000077185:Resveratrol; D006918:Hydroxyurea