A novel Bim-BH3-derived Bcl-X(L) inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity (Articolo in rivista)

Type
Label
  • A novel Bim-BH3-derived Bcl-X(L) inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity (Articolo in rivista) (literal)
Anno
  • 2008-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.4161/cc.7.20.6830 (literal)
Alternative label
  • Ponassi R.; Biasotti B.; Tomati V.; Bruno S.; Poggi A.; Malacarne D.; Cimoli G.; Salis A.; Pozzi S.; Miglino M.; Damonte G.; Cozzini P.; Spyraki F.; Campanini B.; Bagnasco L.; Castagnino N.; Tortolina L.; Mumot A.; Frassoni F.; Daga A.; Cilli M.; Piccardi F.; Monfardini I.; Perugini M.; Zoppoli G.; D'Arrigo C.; Pesenti R.; Parodi S. (2008)
    A novel Bim-BH3-derived Bcl-X(L) inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity
    in Cell cycle (Georget. Tex.)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Ponassi R.; Biasotti B.; Tomati V.; Bruno S.; Poggi A.; Malacarne D.; Cimoli G.; Salis A.; Pozzi S.; Miglino M.; Damonte G.; Cozzini P.; Spyraki F.; Campanini B.; Bagnasco L.; Castagnino N.; Tortolina L.; Mumot A.; Frassoni F.; Daga A.; Cilli M.; Piccardi F.; Monfardini I.; Perugini M.; Zoppoli G.; D'Arrigo C.; Pesenti R.; Parodi S. (literal)
Pagina inizio
  • 3211 (literal)
Pagina fine
  • 3224 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
  • http://www.landesbioscience.com/journals/cc/article/6830/ (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 7 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 20 (literal)
Note
  • ISI Web of Science (WOS) (literal)
  • Scopu (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Bruno S. Univ Genoa, Dept Expt Med, Human Anat Sect, I-16132 Genoa, Italy Ponassi R.; Biasotti B.; Tomati V.;Bagnasco L.; Castagnino N.; Tortolina L.; Mumot A.; Parodi S. Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy Miglino M. Univ Genoa, Div Hematol, I-16132 Genoa, Italy Monfardini I.; Perugini M.; Zoppoli G. Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy Ponassi R.; Biasotti B.; Tomati V.;Bagnasco L.; Castagnino N.; Tortolina L.; Mumot A.; Malacarne D; Parodi S.Natl Canc Inst IST, Expt Oncol Lab, Genoa, Italy Poggi A. Natl Canc Inst IST, Immunol Lab, Genoa, Italy Daga A. Natl Canc Inst IST, Lab Genes Transfer, Genoa, Italy Cilli M.; Piccardi F. Natl Canc Inst IST, Anim Facil, Genoa, Italy Cimoli G. Tecan Italia Srl, Cernusco Sul Naviglio, MI, Italy Salis A.; Damonte G.Ctr Excellence Biomed Res, Dept Expt Med, Biochem Sect, Genoa, Italy Pozzi S.; Frassoni F.San Martino Hosp, Dept Hematol Oncol, Genoa, Italy Cozzini P.; Spyraki F.;Campanini B. Univ Parma, I-43100 Parma, Italy D'Arrigo C. CNR Genoa Area, Inst Macromol Studies, Genoa, Italy Pesenti R. Ca Foscari Univ, Dept Appl Math, Venice, Italy (literal)
Titolo
  • A novel Bim-BH3-derived Bcl-X(L) inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity (literal)
Abstract
  • BH3-only members of the Bcl-2 family exert a fundamental role in apoptosis induction. This work focuses on the development of a novel peptidic molecule based on the BH3 domain of Bim. The antiapoptotic molecule Bcl-X(L), involved in cancer development/progression and tumour resistance to cytotoxic drugs, is a target for Bim. According to a rational study of the structural interactions between wt Bim-BH3 and Bcl-X(L), we replaced specific residues of Bim-BH3 with natural and non-natural aminoacids and added an internalizing sequence, thus increasing dramatically the inhibitory activity of our modified Bim-BH3 peptide, called 072RB. Confocal microscopy and flow cytometry demonstrated cellular uptake and internalization of 072RB, followed by co-localization with mitochondria. Multiparameter flow cytometry demonstrated that the 072RB dose-dependent growth inhibition of leukaemia cell lines was due to apoptotic cell death. No effect was observed when cells were treated with the internalizing vector alone or a mutated control peptide (single aminoacid substitution L94A). Ex-vivo derived leukemic cells from acute myeloid leukaemia (AML) patients underwent cell death when cultured in vitro in the presence of 072RB. Conversely, no significant cytotoxic effect was observed when 072RB was administered to cultures of peripheral blood mononuclear cells, either resting or PHA-stimulated, and bone marrow cells of normal donors. Xenografts of human AML cells in NOD/SCID mice displayed a significant delay of leukemic cell growth upon treatment with 072RB administered intravenously (15 mg/Kg three times, 48 hours after tumour cell injection). Altogether, these observations support the therapeutic potentials of this novel BH3 mimetic. (literal)
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