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

Lisa M Greene, Marina Fleeton, Jude Mulligan, Chikkanna Gowda, Brian J Sheahan, Gregory J Atkins, Giuseppe Campiani, Vito Nacci, Mark Lawler, D Clive Williams, Daniela M Zisterer, Mark Lawler

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21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1357-63
Number of pages7
JournalOncology Reports
Volume14
Issue number5
Publication statusPublished - Nov 2005

Keywords

  • Animals
  • Apoptosis
  • Breast Neoplasms
  • Cell Cycle
  • Cell Survival
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Oxazepines
  • Pyrroles
  • Receptor, ErbB-2
  • Receptors, Estrogen
  • Tumor Cells, Cultured

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