Differential suppression of proliferation in MCF-7 and MDA-MB-231 breast cancer cells exposed to alpha-, gamma- and delta-tocotrienols is accompanied by altered expression of oxidative stress modulatory enzymes

Anticancer Res. 2010 Oct;30(10):4169-76.


Tocotrienols belong to the vitamin E family of chemicals known to have potent anti-proliferative and apoptotic activities against a variety of cancer cells with little to no comparable influence on the normal cells. Whether tocotrienols control the expression of phase II antioxidant enzymes in the context of their anti-carcinogenic mechanisms has not been investigated. The present studies were performed to test whether the differential growth inhibition resulting from exposure to α-, γ- and δ-tocotrienols in estrogen receptor-positive human MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells might be accompanied by changes in phase II antioxidant enzymes. Cell proliferation and clonogenicity in both cell lines were significantly inhibited by γ- and δ-tocotrienols with little affect when cells were similarly exposed to α-tocotrienol, at doses up to 10 μM. The expression and activity of several antioxidant enzymes in 10 μM tocotrienol-treated cells were determined by Western blot and biochemical assays. In MDA-MB-231 cells, δ- was more active than α- or γ-tocotrienols in up-regulating glutathione peroxidase; however, the three tocotrienols had comparable activity in inducing thioredoxin. In MCF-7 cells, expression of quinone reductase 2 and thioredoxin was increased by γ- and δ-tocotrienols, whereas quinone reductase 1 was unaffected by exposure to the tocotrienols. The tocotrienols also did not affect the expression and activity of superoxide dismutase in both MCF-7 and MDA-MB-231 cells, but increased catalase activity concomitant with slight reduction in the catalase expression. In MDA-MB-231 cells, treatment by tocotrienols led to several fold increase of NRF2 expression marked by corresponding decrease in KEAP1 levels. By contrast, no significant change in NRF2 and KEAP1 levels was observed in MCF-7 cells. These studies demonstrate that different tocotrienols show distinct and selective activity in regulating the NRF2-KEAP1, in coordination with the induced expression of cytoprotective oxidative stress modulatory genes and regulation of proliferation in breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Catalase / biosynthesis
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Enzyme Induction / drug effects
  • Female
  • Glutathione Peroxidase / biosynthesis
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • NAD(P)H Dehydrogenase (Quinone) / biosynthesis
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects*
  • Receptors, Estrogen / biosynthesis
  • Receptors, Estrogen / metabolism
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase-1
  • Tocotrienols / pharmacology*


  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Receptors, Estrogen
  • SOD1 protein, human
  • Tocotrienols
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human