Delta-tocotrienol induces apoptotic cell death via depletion of intracellular squalene in ED40515 cells

Food Funct. 2014 Nov;5(11):2842-9. doi: 10.1039/c4fo00635f.

Abstract

Here, we examined the effect of tocotrienols (T3) on the growth of adult T-cell leukemia (ATL) cells. All three forms (β-, γ-, and δ-T3) inhibited cell proliferation in a dose-dependent manner; δ-T3 showed the strongest growth-inhibitory effect. δ-T3 increased the G1, G2/M, and subG1 populations and induced internucleosomal DNA fragmentation. δ-T3 treatment also increased the levels of cleaved caspase-3, -6, -7, -9, and poly-ADP ribose polymerase (PARP), and this was accompanied by downregulation of Bcl-2, Bcl-xL, and XIAP. Moreover, δ-T3 decreased nuclear p65 NF-κB levels, indicating downregulation of NF-κB activity. This cytotoxic effect of δ-T3 was abrogated by squalene (SQL) but not mevalonate (MVL), farnesyl diphosphate (FPP), geranylgeranyl diphosphate (GGPP), or cholesterol (CL). δ-T3 decreased intracellular SQL levels, and inhibition of de novo cholesterol synthesis did not affect the action of SQL. Furthermore, δ-T3 significantly decreased farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. Taken together, it is evident that δ-T3, due to its ability to potently induce apoptosis via the depletion of intracellular SQL, shows the potential to be considered a therapeutic agent in patients with ATL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Caspase 6 / metabolism
  • Caspase 7 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects
  • Down-Regulation
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism
  • Humans
  • Squalene / metabolism*
  • Transcription Factor RelA / metabolism
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • BAX protein, human
  • BCL2L1 protein, human
  • RELA protein, human
  • Transcription Factor RelA
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Vitamin E
  • tocotrienol, delta
  • Squalene
  • Farnesyl-Diphosphate Farnesyltransferase
  • CASP3 protein, human
  • CASP6 protein, human
  • CASP7 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 6
  • Caspase 7
  • Caspase 9