Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia.
The effects of the hyperforin (HF), a natural phloroglucinol purified from Hypericum perforatum, were investigated ex vivo on leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL). HF was found to promote apoptosis of B-CLL cells, as shown by time- and dose-dependent stimulation of phosphatidylserine externalization and DNA fragmentation, by disruption of the mitochondrial transmembrane potential, caspase-3 activation and cleavage of the caspase substrate PARP-1. Moreover, HF-induced downregulation of Bcl-2 and Mcl-1, two antiapoptotic proteins that control mitochondrial permeability. HF also downregulated two proteins which are overexpressed by B-CLL patients' cells, the cell cycle inhibitor p27kip1 through caspase-dependent cleavage into a p23 form, and the nitric oxid (NO) synthase of type 2 (inducible NO synthase). This latter was accompanied by reduction in the production of NO known to be antiapoptotic in B-CLL cells. Preventing effects of the general caspase inhibitor z-VAD-fmk indicated that HF-promoted apoptosis of B-CLL cells was mostly caspase dependent. Furthermore, normal B lymphocytes purified from healthy donors appeared less sensitive to HF-induced apoptosis than B-CLL cells. These results indicate that HF may be of interest in the development of new therapies for B-CLL based on the induction of apoptosis and combination with cell cycle-dependent antitumor drugs.
Quiney
C
C
UMR 736 INSERM/Université Paris VI, Centre de Recherches Biomédicales des Cordeliers, Paris, France.
Billard
C
C
Faussat
A M
AM
Salanoubat
C
C
Ensaf
A
A
Naït-Si
Y
Y
Fourneron
J D
JD
Kolb
J-P
JP
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D013729:Terpenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009569:Nitric Oxide; D010696:Phloroglucinol; D052247:Nitric Oxide Synthase Type II; D020169:Caspases; C001654:hyperforin