The BH3-only protein Noxa is stimulated during apoptosis of chronic lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract

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BlankThe BH3-only protein Noxa is stimulated during apoptosis of chronic

lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract.

M Zaher, M Mirshahi, Y Nuraliev, M Sharifova, I Bombarda, JP Marie, and C

Billard

Int J Oncol, July 12, 2011; .

Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.

Deficiency of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL)

cells. M2Yn is a natural extract from plants of central Asia, identified for its

antiangiogenic properties and its ability to block the migration of malignant

cells. Here, we report that in vitro treatment of cells derived from CLL

patients with M2Yn results in internucleosomal DNA fragmentation,

phosphatidylserine externalization, mitochondrial membrane depolarization,

caspase-3 activation and cleavage of the caspase substrate PARP-1. The extents

of these effects depend on the patients and are mostly comparable to those of

flavopiridol or hyperforin, two known plant-derived apoptosis inducers of CLL

cells. M2Yn does not modulate Mcl-1 expression, while downregulation of this

antiapoptotic protein is involved in the action of flavopiridol. By contrast,

M2Yn, like hyperforin, upregulates the Noxa protein, possibly by inhibiting

proteasomal activity. This BH3-only protein is known to trigger the activation

of the pro-apoptotic protein Bak through displacement of the Mcl-1/Bak complex

at the mitochondrial membrane, as actually observed here in M2Yn-treated cells.

Our data, therefore, show that M2Yn can induce the caspase-dependent

mitochondrial pathway of apoptosis in CLL cells via a mechanism resembling that

of hyperforin. Our data also confirm that the BH3-only protein Noxa is a

relevant target for CLL therapy.

PMID: 21750864