[Potentiation of arsenic trioxide-induced apoptosis by retinoic acid in retinoic acid sensitive and resistant HL-60 myeloid leukemia cells]

Chin Med J (Engl). 2000 Jun;113(6):498-501.
[Article in Chinese]

Abstract

Objective: To study the effect of arsenic trioxide (As2O3) on non-APL acute myeloid leukemia (AML) cells and the interreactive effect between retinoic acid (RA) and As2O3.

Methods: RA-sensitive (S) and RA-resistant (R) HL-60 non-APL AML cells were used as an in vitro model. Cell number and trypan blue were used to observe cell growth and survival. Apoptosis was determined by morphological changes, using a DNA laddering assay, terminal deoxynucleotidyl transferase (TdT) fragment end labeling assay and a flow cytometry assay.

Results: As2O3 induced apoptosis in both HL-60S and HL-60R cells, As2O3-induced apoptosis was both time- and concentration-dependent in a therapeutically-achievable As2O3 range (0.25-4.0 mumol/L). Both all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9cRA) potentiated As2O3-induced apoptosis, as measured by quantitative TdT fragment and labeling and flow cytometry assays in both HL-60S and HL-60R cells (P < 0.05, for all RA + As2O3 combinations vs As2O3 alone in both sublines).

Conclusions: As2O3 may inhibit the growth of non-APL AML cells by promoting programmed cell death. RA can potentiate As2O3-induced apoptosis even in RA-resistant HL-60 cells in which the classical ATRA response pathway is repressed owing to a homozygous inactivating mutation in the retinoic acid receptor alpha. As2O3 can have clinical activity in non-APL cases of AML and the enhanced activity might result from the combined As2O3-RA therapy.

MeSH terms

  • Alitretinoin
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Cell Division / drug effects
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • HL-60 Cells / drug effects
  • Humans
  • Oxides / pharmacology*
  • Tretinoin / pharmacology*

Substances

  • Antineoplastic Agents
  • Arsenicals
  • Oxides
  • Alitretinoin
  • Tretinoin
  • Arsenic Trioxide