title: Effect of sesquiterpene lactone coronopilin on leukaemia cell population growth, cell type-specific induction of apoptosis and mitotic catastrophe.
abstract: OBJECTIVE
  The aim of this study was to investigate anti-leukaemic potential of coronopilin, a sesquiterpene lactone from Ambrosia arborescens, and to characterize mechanism(s) underlying its activity.
  
  
  METHODS
  The study was conducted on Jurkat and U937, two leukaemia-derived cell lines. Apoptosis and impairment of cell cycle progression were evaluated by flow cytometry and by microscopic analysis. Changes in protein expression and activation were evaluated by western blot analysis. Coronopilin-tubulin covalent adducts were demonstrated by mass spectrometry.
  
  
  RESULTS
  Coronopilin inhibited (IC(50) ≤ 20 μm) leukaemia cell population growth, but displayed poor cytotoxicity to normal white blood cells. On Jurkat cells, coronopilin exerted cell population growth inhibition activity, mainly by triggering caspase-dependent apoptosis. Conversely, in U937 cells, coronopilin's primary response was a robust arrest in G(2) /M. Marked increase in mitotic index and presence of activated cyclin B1/Cdk1 complex, phosphorylated histone H3 at Ser10, and hyperpolymerized tubulin indicated that cells accumulated in mitosis. Prolonged mitotic arrest ultimately resulted in U937 mitotic catastrophe, and dying cells exhibited the features of non-caspase-dependent death.
  
  
  CONCLUSIONS
  This study demonstrated that coronopilin efficiently inhibited leukaemia cell population growth by triggering cell type-specific responses. Moreover, coronopilin-mediated cell population expansion inhibition was specific to neoplastic cells, as normal white blood cell viability was not significantly affected. Thus, coronopilin may represent an interesting new chemical scaffold upon which to develop new anti-leukaemic agents.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Salerno, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cotugno
authors.forename: R
authors.initials: R
authors.lastname: Fortunato
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.forename: D
authors.initials: D
authors.lastname: Gallotta
authors.forename: A
authors.initials: A
authors.lastname: Braca
authors.forename: N
authors.initials: N
authors.lastname: De Tommasi
authors.forename: M A
authors.initials: MA
authors.lastname: Belisario
mesh_terms: D031164:Ambrosia / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D055808:Drug Discovery; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D008517:Phytotherapy; D010946:Plants, Medicinal / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012717:Sesquiterpenes; D014404:Tubulin; D020169:Caspases