临床可达到浓度的12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯与全反式维甲酸、1α,25 - 二羟基维生素D3和丁酸钠联合对HL - 60细胞分化的协同作用。

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.

作者信息

Zheng X, Chang R L, Cui X X, Kelly K A, Shih W J, Lin Y, Strair R, Suh J, Han Z T, Rabson A, Conney A H

机构信息

Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USA.

出版信息

Oncol Res. 2000;12(9-10):419-27.

PMID:11697820

Abstract

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.

摘要

我们最近的研究表明，12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）对治疗急性髓细胞白血病患者具有药理活性。在本研究中，我们研究了全反式维甲酸（RA）、1α,25 - 二羟基维生素D3（VD3）和丁酸钠（NaB）对TPA诱导HL - 60人早幼粒细胞白血病细胞分化的潜在协同作用。细胞用这些试剂处理一次，持续48小时，或每24小时处理一次，持续96小时。用TPA、RA、VD3或NaB对HL - 60细胞处理一次，持续48小时，导致浓度依赖性生长抑制和细胞分化。在临床可达到的浓度下，TPA（0.16 nM）增加了贴壁细胞的数量，RA（0.1 - 1 microM）增加了硝基蓝四氮唑（NBT）阳性细胞的数量。TPA（0.16 nM）与RA（0.1 - 1 microM）、VD3（1 nM）或NaB（100 microM）组合处理48小时，通过贴壁细胞的形成来衡量，协同增加了分化（P≤0.01）。此外，每24小时用低浓度的TPA、RA、VD3和NaB的各种组合处理细胞96小时，导致细胞生长进一步减少和分化增加。在临床可达到的浓度下，用结合TPA、RA、VD3和NaB的“鸡尾酒”处理的细胞实现了最强的分化刺激。TPA与RA或NaB在临床有效浓度下组合对HL - 60细胞分化的协同作用表明，这些试剂的组合可能提高TPA治疗急性早幼粒细胞白血病（APL）患者的疗效。结合TPA、RA、VD3和NaB的分化“鸡尾酒”可能为提高TPA和RA的治疗效果提供一种更有效的策略。