Weinberg J B, Mason S N
VA Medical Center, Division of Hematology/Oncology, Durham, North Carolina 27705.
Cancer Res. 1991 Feb 15;51(4):1202-9.
We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells. This study was designed to determine the effects of acivicin on the levels of HL-60 cell mRNA transcripts of several cytokines, growth factors, and protooncogenes implicated in the control of hematopoietic cell proliferation and differentiation. Control HL-60 cells did not express mRNA for granulocyte-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor, interleukin 3, or interleukin 6, and acivicin or phorbol myristate acetate did not induce their expression. Phorbol myristate acetate reduced expression of c-myc, c-myb, and heat shock protein 70 and enhanced those of macrophage-colony-stimulating factor and c-fms. Acivicin caused a decreased expression of c-myc, and an increased expression of mRNA for interleukin 1 beta and tumor necrosis factor alpha (TNF-alpha). The drug also caused an initial increase in c-myb, followed by a subsequent decrease below baseline levels. Supernatants and lysates of acivicin-treated HL-60 cells contained increased levels of interleukin 1 beta. Both TNF-alpha and interleukin 1 beta have been shown previously to influence hematopoietic cell differentiation. In our experiments, exogenous interleukin 1 added to HL-60 cells did not induce differentiation, but the combination of interleukin 1 and TNF synergistically enhanced the process. Pretreatment of the cells with TNF enhanced their responsiveness to subsequent treatment with interleukin 1. Our results demonstrate that the glutamine antagonist acivicin modulates HL-60 cell expression of TNF-alpha, interleukin 1 beta, c-myc, and c-myb and suggest that interleukin 1 beta and TNF-alpha might (in an autocrine manner) cause the differentiation.
我们之前已经注意到谷氨酰胺拮抗剂阿西维辛（αS，5S-α-氨基-3-氯-4，5-二氢-5-异恶唑乙酸）可诱导新鲜分离的人髓系白血病细胞和HL-60细胞发生单核细胞样分化。本研究旨在确定阿西维辛对几种细胞因子、生长因子和原癌基因的HL-60细胞mRNA转录水平的影响，这些因子与造血细胞增殖和分化的控制有关。对照HL-60细胞不表达粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子、白细胞介素3或白细胞介素6的mRNA，阿西维辛或佛波酯肉豆蔻酸酯也不诱导它们的表达。佛波酯肉豆蔻酸酯降低了c-myc、c-myb和热休克蛋白70的表达，并增强了巨噬细胞集落刺激因子和c-fms的表达。阿西维辛导致c-myc表达降低，白细胞介素1β和肿瘤坏死因子α（TNF-α）的mRNA表达增加。该药物还导致c-myb最初增加，随后降至基线水平以下。阿西维辛处理的HL-60细胞的上清液和裂解物中白细胞介素1β水平升高。TNF-α和白细胞介素1β之前均已被证明可影响造血细胞分化。在我们的实验中，添加到HL-60细胞中的外源性白细胞介素1不诱导分化，但白细胞介素1和TNF的组合协同增强了这一过程。用TNF预处理细胞增强了它们对随后白细胞介素1处理的反应性。我们的结果表明，谷氨酰胺拮抗剂阿西维辛调节HL-60细胞中TNF-α、白细胞介素1β、c-myc和c-myb的表达，并提示白细胞介素1β和TNF-α可能（以自分泌方式）导致分化。
