Synergistic effects of clinically achievable concentrations of 12-O-tetradecanoylphorbol-13-acetate in combination with all-trans retinoic acid, 1alpha,25-dihydroxyvitamin D3, and sodium butyrate on differentiation in HL-60 cells.
Our recent studies demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) has pharmacological activity for the treatment of acute myelocytic leukemia patients. In the present study, we investigated the potential synergistic effect of all-trans retinoic acid (RA), 1alpha,25-dihydroxyvitamin D3 (VD3), and sodium butyrate (NaB) on TPA-induced differentiation in HL-60 human promyelocytic leukemia cells. The cells were treated once with these agents for 48 h or treated every 24 h for 96 h. Treatment of HL-60 cells once with TPA, RA, VD3, or NaB for 48 h resulted in concentration-dependent growth inhibition and cell differentiation. At clinically achievable concentrations, TPA (0.16 nM) increased the number of adherent cells and RA (0.1-1 microM) increased the number of nitroblue tetrazolium (NBT)-positive cells. The combinations of TPA (0.16 nM) with RA (0.1-1 microM), VD3 (1 nM), or NaB (100 microM) for 48 h synergistically increased differentiation as measured by the formation of adherent cells (P < or = 0.01). Moreover, cells treated with various combinations of low concentrations of TPA, RA, VD3, and NaB every 24 h for 96 h resulted in a further decrease in cell growth and an increase in differentiation. At clinically achievable concentrations, the strongest stimulation of differentiation was achieved in cells treated with a "cocktail" that combined TPA, RA, VD3, and NaB. The synergistic effect of combinations of TPA with RA or NaB at clinically effective concentrations on HL-60 cell differentiation suggests that the combination of these agents may improve the therapeutic efficacy of TPA for the treatment of acute promyelocytic leukemia (APL) patients. A differentiation "cocktail" that combines TPA, RA, VD3, and NaB may provide an even more effective strategy for improving the therapeutic efficacy of TPA and RA.
Zheng
X
X
Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USA.
Chang
R L
RL
Cui
X X
XX
Kelly
K A
KA
Shih
W J
WJ
Lin
Y
Y
Strair
R
R
Suh
J
J
Han
Z T
ZT
Rabson
A
A
Conney
A H
AH
D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002273:Carcinogens; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D007202:Indicators and Reagents / Q000494:pharmacology; D009153:Mutagens; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D012978:Sodium Oxybate / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018686:Anesthetics, Intravenous; D000970:Antineoplastic Agents; D002120:Calcium Channel Agonists; D002273:Carcinogens; D007202:Indicators and Reagents; D009153:Mutagens; D009580:Nitroblue Tetrazolium; D014212:Tretinoin; D012978:Sodium Oxybate; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate