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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
Zheng
X, Chang RL, Cui XX, Kelly KA, Shih WJ, Lin Y, Strair R, Suh J, Han ZT, Rabson
A, Conney AH
Department
of Chemical Biology, College of Pharmacy, Rutgers, The State University of New
Jersey, Piscataway 08854, USA.
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.
PMID:
11697820 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11697820&dopt=Abstract
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