title: Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells.
abstract: OBJECTIVE
  Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls) induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians.
  
  
  METHODS
  We examined leafy galls fraction F3.1.1 on cell proliferation, cell division and cytoskeletal disorganization of human cancer cell lines using time-lapse videomicroscopy imaging, combined with flow cytometry and immunofluorescence analysis. We determined the F3.1.1-fraction composition by gas chromatography coupled to mass spectrometry.
  
  
  RESULTS
  The leafy galls induced on tobacco by R. fascians yielded fraction F3.1.1 which inhibited proliferation of glioblastoma U373 cells with an IC50 of 4.5 µg/mL, F.3.1.1 was shown to increase cell division duration, cause nuclear morphological deformations and cell enlargement, and, at higher concentrations, karyokinesis defects leading to polyploidization and apoptosis. F3.1.1 consisted of a mixture of isomers belonging to the cembrenoids. The cellular defects induced by F3.1.1 were caused by a peculiar cytoskeletal disorganization, with the occurrence of fragmented tubulin and strongly organized microtubule aggregates within the same cell. Colchicine, paclitaxel, and cembrene also affected U373 cell proliferation and karyokinesis, but the induced microtubule rearrangement was very different from that provoked by F3.1.1. Altogether our data indicate that the cembrenoid isomers in F3.1.1 have a unique mode of action and are able to simultaneously modulate microtubule polymerization and stability.
authors.affiliation: Laboratoire de Toxicologie, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Aminata P
authors.initials: AP
authors.lastname: Nacoulma
authors.forename: Veronique
authors.initials: V
authors.lastname: Megalizzi
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Pottier
authors.forename: Manuela
authors.initials: M
authors.lastname: De Lorenzi
authors.forename: Sylviane
authors.initials: S
authors.lastname: Thoret
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Vandeputte
authors.forename: Pierre
authors.initials: P
authors.lastname: Duez
authors.forename: Danny
authors.initials: D
authors.lastname: Vereecke
authors.forename: Mondher
authors.initials: M
authors.lastname: El Jaziri
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010935:Plant Diseases; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D012240:Rhodococcus; D014026:Nicotiana / Q000737:chemistry / Q000382:microbiology
chemical_list: D004224:Diterpenes; D010936:Plant Extracts