4-Arylcoumarin analogues of combretastatins stimulate apoptosis of leukemic cells from chronic lymphocytic leukemia patients.

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4-Arylcoumarin analogues of combretastatins stimulate apoptosis of leukemic

cells from chronic lymphocytic leukemia patients.

Christian Billard, Faouzia Menasria, Quiney, Anne-Marie Faussat,

Jean-Pierre Finet, Sebastien Combes, and Jean-Pierre Kolb

Exp Hematol, October 13, 2008; .

UMRS 872 INSERM, Université Pierre et Marie Curie-Paris 6 and Université Paris

Descartes, Equipe 18, Centre de Recherche des Cordeliers, Paris, France.

OBJECTIVE: To investigate the proapoptotic capacities of four arylcoumarin

analogues of combretastatins on leukemic cells from B-cell chronic lymphocytic

leukemia (CLL), a malignancy characterized by apoptosis deficiency. MATERIALS

AND METHODS: The effects of the four compounds on several nuclear, membrane, and

mitochondrial events of apoptosis and on expression of proteins controlling the

apoptosis were analyzed after treatment of cultured CLL patients' cells.

RESULTS: Treatment with all four compounds resulted in a dose-dependent

internucleosomal DNA fragmentation, in stimulation of phosphatidylserine

externalization, disruption of the mitochondrial transmembrane potential and

caspase-3 activation. DNA fragmentation was prevented in the presence of the

pan-caspase inhibitor z-VAD-fmk. Two of the compounds downregulated the

expression of Mcl-1, a protein thought to be crucial for the antiapoptotic state

in CLL, while Bcl-2 expression was unaffected. No effects were observed on the

expression of p27(kip1) or the inducible nitric oxide synthase, two proteins,

which are constitutively overexpressed by CLL cells and downregulated during the

apoptosis induced by other plant-derived molecules (flavopiridol, polyphenols,

or hyperforin). This suggests different mechanisms of action for the compounds

studied here. Furthermore, normal B lymphocytes from healthy donors appeared

less sensitive than CLL cells to the proapoptotic activity of the four

compounds. CONCLUSION: The four arylcoumarin analogues were able to promote the

apoptosis of CLL cells ex vivo through the caspase-dependent mitochondrial

pathway. Therefore, these compounds may be of interest to develop new therapies

of CLL based on apoptosis restoration.

PMID: 18922614