title: The BH3-only protein Noxa is stimulated during apoptosis of chronic lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract.
abstract: 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.
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.|Université Pierre et Marie Curie, UMRS 872, Paris, France|Université Paris-Descartes, UMRS 872, Paris, France
authors.forename: Murhaf
authors.initials: M
authors.lastname: Zaher
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.|Université Pierre et Marie Curie, UMRS 872, Paris, France|Université Paris-Descartes, UMRS 872, Paris, France|Academy of Sciences, Dushanbe, Tajikistan
authors.forename: Massoud
authors.initials: M
authors.lastname: Mirshahi
authors.affiliation: International Institute for Avicenna Heritage and Pharmacology, Dushanbe, Tajikistan
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Nuraliev
authors.affiliation: International Institute for Avicenna Heritage and Pharmacology, Dushanbe, Tajikistan
authors.forename: Mizhgona
authors.initials: M
authors.lastname: Sharofova
authors.affiliation: ISM2-AD2M, UMR CNRS 6263, Université Paul Cézanne, Marseille, France
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bombarda
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.|Université Pierre et Marie Curie, UMRS 872, Paris, France|Université Paris-Descartes, UMRS 872, Paris, France|Département d'Hématologie, Hôpital Saint-Antoine, Paris, France
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.affiliation: Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.|Université Pierre et Marie Curie, UMRS 872, Paris, France|Université Paris-Descartes, UMRS 872, Paris, France
authors.forename: Christian
authors.initials: C
authors.lastname: Billard
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D010718:Phosphatidylserines; D010880:Piperidines; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D013729:Terpenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; C077990:alvocidib; D010696:Phloroglucinol; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C001654:hyperforin