title: Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells.
abstract: BACKGROUND
  We previously demonstrated that the plant-derived agent α-bisabolol enters cells via lipid rafts, binds to the pro-apoptotic Bcl-2 family protein BID, and may induce apoptosis. Here we studied the activity of α-bisabolol in acute leukemia cells.
  
  
  METHODS
  We tested ex vivo blasts from 42 acute leukemias (14 Philadelphia-negative and 14 Philadelphia-positive B acute lymphoid leukemias, Ph-/Ph+B-ALL; 14 acute myeloid leukemias, AML) for their sensitivity to α-bisabolol in 24-hour dose-response assays. Concentrations and time were chosen based on CD34+, CD33+my and normal peripheral blood cell sensitivity to increasing α-bisabolol concentrations for up to 120 hours.
  
  
  RESULTS
  A clustering analysis of the sensitivity over 24 hours identified three clusters. Cluster 1 (14 ± 5 μM α-bisabolol IC50) included mainly Ph-B-ALL cells. AML cells were split into cluster 2 and 3 (45 ± 7 and 65 ± 5 μM IC50). Ph+B-ALL cells were scattered, but mainly grouped into cluster 2. All leukemias, including 3 imatinib-resistant cases, were eventually responsive, but a subset of B-ALL cells was fairly sensitive to low α-bisabolol concentrations. α-bisabolol acted as a pro-apoptotic agent via a direct damage to mitochondrial integrity, which was responsible for the decrease in NADH-supported state 3 respiration and the disruption of the mitochondrial membrane potential.
  
  
  CONCLUSIONS
  Our study provides the first evidence that α-bisabolol is a pro-apoptotic agent for primary human acute leukemia cells.
authors.affiliation: Department of Medicine, Section of Hematology, University of Verona, Italy. fabrizio.vinante@univr.it
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cavalieri
authors.forename: Antonella
authors.initials: A
authors.lastname: Rigo
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonifacio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carcereri de Prati
authors.forename: Emanuele
authors.initials: E
authors.lastname: Guardalben
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pizzolo
authors.forename: Hisanori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vinante
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001549:Benzamides; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology; D001773:Blood Cells / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D016000:Cluster Analysis; D003470:Culture Media; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D000081222:Monocyclic Sesquiterpenes; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013997:Time Factors; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D001549:Benzamides; D003470:Culture Media; D000081222:Monocyclic Sesquiterpenes; D010879:Piperazines; D011743:Pyrimidines; D012717:Sesquiterpenes; C004497:bisabolol; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl