The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells

Biochem Biophys Res Commun. 2002 Aug 30;296(4):942-8. doi: 10.1016/s0006-291x(02)02014-4.

Abstract

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / pharmacology
  • Apoptosis*
  • Blotting, Western
  • Breast Neoplasms / pathology*
  • Caspase 3
  • Caspase 7
  • Caspase 9
  • Caspases / biosynthesis
  • Caspases / metabolism
  • Cell Division
  • Chemotactic Factors / pharmacology
  • Cytochrome c Group / metabolism
  • Cytosol / metabolism
  • DNA / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Hydroxyeicosatetraenoic Acids / pharmacology
  • Lipoxygenase Inhibitors / pharmacology*
  • Mitogens
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / biosynthesis
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Tumor Cells, Cultured

Substances

  • Chemotactic Factors
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Lipoxygenase Inhibitors
  • Mitogens
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • 5-hydroxy-6,8,11,14-eicosatetraenoic acid
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • DNA
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • CASP7 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 7
  • Caspase 9
  • Caspases