Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitro

Biochem Pharmacol. 2000 Jul 15;60(2):221-31. doi: 10.1016/s0006-2952(00)00319-1.


The dietary isothiocyanates and cancer chemopreventive agents phenethyl isothiocyanate and allyl isothiocyanate and their cysteine conjugates inhibited the growth and induced apoptosis of human leukaemia HL60 (p53-) and human myeloblastic leukaemia-1 cells (p53+) in vitro. The median growth inhibitory concentration (GC(50)) values were in the range 1.49-3.22 microM in cultures with 10% serum. Isothiocyanates and cysteine conjugates had increased potency against HL60 cells in serum-free medium, with GC(50) values of 0.8-0. 9 microM. The potency of the compounds decreased with increased serum content of the medium, but that of the cysteine conjugates decreased more markedly. Growth inhibition and toxicity was characterised by either a rapid interaction of the isothiocyanate with the cells in the first hour of culture or exposure to isothiocyanate liberated from the cysteine conjugate in the initial 3 hr of culture, inhibition of macromolecule synthesis, and a commitment to apoptosis which developed in the initial 24 hr. Activities of caspase-3 and caspase-8 were increased during isothiocyanate-induced apoptosis, but caspase-1 activity was not. The general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and the specific caspase-8 inhibitor N-benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone inhibited apoptosis, but specific caspase-1 and caspase-3 inhibitors did not. The antiproliferative activities were limited by hydrolysis of the isothiocyanate. This suggests that caspase-8 has a critical role, and caspase-3 a supporting role, in isothiocyanate-induced apoptosis in which p53 is not an obligatory participant. Isothiocyanate-induced apoptosis may suppress the growth of preclinical tumours and contribute to the well-established decreased cancer incidence associated with a vegetable-rich diet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / chemistry
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cell Division / drug effects
  • Chemoprevention
  • Cysteine / chemistry
  • Cysteine / pharmacology*
  • DNA, Neoplasm / biosynthesis
  • Diet*
  • Food Preservatives / pharmacology
  • HL-60 Cells
  • Humans
  • Hydrolysis
  • Isothiocyanates / chemistry
  • Isothiocyanates / pharmacology*
  • Leukemia
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • RNA, Neoplasm / biosynthesis
  • Tumor Cells, Cultured


  • Anticarcinogenic Agents
  • DNA, Neoplasm
  • Food Preservatives
  • Isothiocyanates
  • RNA, Neoplasm
  • phenethyl isothiocyanate
  • allyl isothiocyanate
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • Cysteine