title: The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo.
abstract: Members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds have been shown to induce apoptosis in a number of human leukemia cell lines of different haematological lineage, suggesting their potential as anti-cancer agents. In this study, we sought to determine if PBOX-6, a well characterised member of the PBOX series of compounds, is also an effective inhibitor of breast cancer growth. Two estrogen receptor (ER)-positive (MCF-7 and T-47-D) and two ER-negative (MDA-MB-231 and SK-BR-3) cell lines were examined. The 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to determine reduction in cell viability. PBOX-6 reduced the cell viability of all four cell lines tested, regardless of ER status, with IC(50) values ranging from 1.0 to 2.3 microM. PBOX-6 was most effective in the SK-BR-3 cells, which express high endogenous levels of the HER-2 oncogene. Overexpression of the HER-2 oncogene has been associated with aggressive disease and resistance to chemotherapy. The mechanism of PBOX-6-induced cell death was due to apoptosis, as indicated by the increased proportion of cells in the pre-G1 peak and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, intratumoural administration of PBOX-6 (7.5 mg/kg) significantly inhibited tumour growth in vivo in a mouse mammary carcinoma model (p=0.04, n=5, Student's t-test). Thus, PBOX-6 could be a promising anti-cancer agent for both hormone-dependent and -independent breast cancers.
authors.affiliation: Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Marina
authors.initials: M
authors.lastname: Fleeton
authors.forename: Jude
authors.initials: J
authors.lastname: Mulligan
authors.forename: Chikkanna
authors.initials: C
authors.lastname: Gowda
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sheahan
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010077:Oxazepines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology; D011960:Receptors, Estrogen / Q000032:analysis* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D010077:Oxazepines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C418868:PBOX-6