[Potentiation of arsenic trioxide-induced apoptosis by retinoic acid in retinoic acid sensitive and resistant HL-60 myeloid leukemia cells].
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.
Huang
X
X
Institute of Hematology, People's Hospital, Beijing Medical University, Beijing 100044, China.
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077556:Alitretinoin; D014212:Tretinoin; D000077237:Arsenic Trioxide