Sokoloski J A, Sartorelli A C
Department of Pharmacology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Leuk Res. 1998 Feb;22(2):153-61. doi: 10.1016/s0145-2126(97)00156-2.
Previous experiments have shown that a variety of agents that interfere with the activity of the transcription factor NF-kB significantly enhanced the differentiation of HL-60 leukemia cells when combined with low levels of the monocytic/macrophagic differentiating agent vitamin D3. These include an antisense phosphorothioate oligonucleotide to the Rel A subunit of NF-kB, vitamin E and other antioxidants, and curcumin. Acetylsalicylic acid and other nonsteroidal anti-inflammatory agents represent another group of agents that have been reported to inhibit NF-kB at serum levels approximating those obtained during long-term therapy of chronic inflammatory states. To determine whether nonsteroidal anti-inflammatory agents also were capable of enhancing the differentiation of HL-60 leukemia cells produced by vitamin D3, we measured the effects of a variety of nonsteroidal anti-inflammatory agents on the maturation of HL-60 cells produced by low levels of vitamin D3. Acetylsalicylic acid by itself had no significant effect on the differentiation of HL-60 cells; however, this agent markedly increased the degree of differentiation produced by low levels of vitamin D3. Furthermore, a variety of other nonsteroidal anti-inflammatory agents of different chemical classes exhibited similar enhancements of the maturation of HL-60 cells when combined with vitamin D3. An analogous increase in the differentiation of HL-60 cells was also obtained by combination of several nonsteroidal anti-inflammatory agents with the granulocytic inducing agent, retinoic acid, but not with dimethylsulfoxide. The nonsteroidal anti-inflammatory agents also enhanced the differentiation of HL-60 cells when combined with vitamin D analogs which share the receptor binding properties of vitamin D3; however, a vitamin D analog which caused significant calcium mobilization, but was less effective in receptor binding than vitamin D3, did not induce the differentiation of HL-60 cells in the presence or absence of anti-inflammatory agents. The findings suggest that the nonsteroidal anti-inflammatory agents may have utility in the treatment of acute promyelocytic leukemia when used with the D vitamins or retinoic acid.
先前的实验表明，多种干扰转录因子NF-κB活性的试剂，与低水平的单核细胞/巨噬细胞分化剂维生素D3联合使用时，能显著增强HL-60白血病细胞的分化。这些试剂包括针对NF-κB的Rel A亚基的反义硫代磷酸酯寡核苷酸、维生素E和其他抗氧化剂，以及姜黄素。乙酰水杨酸和其他非甾体抗炎药是另一类据报道在血清水平接近慢性炎症状态长期治疗期间所达到的水平时能抑制NF-κB的试剂。为了确定非甾体抗炎药是否也能够增强维生素D3诱导的HL-60白血病细胞的分化，我们测量了多种非甾体抗炎药对低水平维生素D3诱导的HL-60细胞成熟的影响。乙酰水杨酸本身对HL-60细胞的分化没有显著影响；然而，该试剂显著增加了低水平维生素D3诱导的分化程度。此外，多种不同化学类别的其他非甾体抗炎药与维生素D3联合使用时，对HL-60细胞的成熟表现出类似的增强作用。几种非甾体抗炎药与粒细胞诱导剂维甲酸联合使用时，也能使HL-60细胞的分化类似地增加，但与二甲基亚砜联合使用时则不然。非甾体抗炎药与具有维生素D3受体结合特性的维生素D类似物联合使用时，也能增强HL-60细胞的分化；然而，一种能引起显著钙动员但在受体结合方面比维生素D3效果差的维生素D类似物，在有或没有抗炎药存在的情况下都不能诱导HL-60细胞的分化。这些发现表明，非甾体抗炎药与D族维生素或维甲酸联合使用时，可能在急性早幼粒细胞白血病的治疗中具有实用价值。
