Hexamethylene bisacetamide-induced differentiation of transformed cells: molecular and cellular effects and therapeutic application.
Hexamethylene bisacetamide-induced differentiation of transformed cells: molecular and cellular effects and therapeutic application.
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六亚甲基双乙酰胺诱导转化细胞分化：分子和细胞效应及治疗应用。
DOI：
10.1002/stem.5530060402
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Rifkind,RA
中科院分区：
文献类型：
--
作者：
Marks,PA;Rifkind,RA
六亚甲基二乙酰胺（HMBA）是一种高极性化合物，可诱导小鼠红白血病（MEL）细胞表达红细胞表型，包括增殖停止。诱导剂介导的MEL（DS 19）细胞分化是一个多步骤的过程，其特征在于潜伏期，在此期间发生许多变化，包括离子通量的改变、膜结合蛋白激酶C（PKC）活性的增加、胞质溶胶中Ca 2+和磷脂非依赖性PKC活性的出现以及许多基因如c-myc、c-myb、HMBA介导的终末分化定型在约12小时时首次检测到，并以随机方式增加，直到超过95%的群体在48至60小时被募集至终末分化。定型与c-myb基因表达的持续抑制有关，到36 ~ 48小时，珠蛋白基因的转录增加了10 ~ 30倍，而rRNA基因的转录受到抑制。类固醇地塞米松或肿瘤促进剂佛波醇-12-肉豆蔻酸酯-13-乙酸酯（TPA）抑制HMBA诱导的MEL细胞终末分化。这些药物似乎在潜伏期的后期起作用。通过选择长春新碱耐药来源于DS 19的MEL细胞系：1）诱导定型而无可检测的潜伏期，2）对HMBA明显更敏感，3）对地塞米松或TPA抑制HMBA诱导定型具有耐药性。这些数据表明，长春新碱耐药MEL细胞表达一种因子，该因子可规避HMBA介导的基本早期事件。HMBA的体外研究为HMBA应用于人类癌症的临床治疗提供了基础。HMBA的临床试验已经启动。
Hexamethylene bisacetamide (HMBA), a highly polar compound, induces murine erythroleukemia (MEL) cells to express the erythroid phenotype, including cessation of proliferation. Inducer-mediated differentiation of MEL (DS19) cells is a multistep process characterized by a latent period during which a number of changes occur including alterations in ion flux, an increase in membrane-bound protein kinase C (PKC) activity, the appearance of Ca2+and phospholipid-independent PKC activity in the cytosol, and modulation in expression of a number of genes such as c-myc,c-myb,c-fos and the p53 genes.HMBA-mediated commitment to terminal differentiation is first detected at about 12 hours and increases in a stochastic fashion until over 95% of the population is recruited to terminal differentiation by 48 to 60 hours. Commitment is associated with persistent suppression of c-myb gene expression.By 36 to 48 hours, transcription of the globin genes has increased 10 to 30 fold, whereas transcription from rRNA genes is suppressed. The steroid, dexamethasone, or the tumor promoter, phorbol-12-myristate-13-acetate (TPA), suppress HMBA-induced MEL cell terminal differentiation. These agents appear to act at a late step during the latent period. MEL cell lines derived from DS19 by selection for resistance to vincristine are: 1) induced to commit without a detectable latent period, 2) markedly more sensitive to HMBA, and 3) resistant to dexamethasone or TPA inhibition of HMBA-induced commitment. The data suggests that vincristine-resistant MEL cells express a factor which circumvents essential HMBA-mediated early events. In vitro studies with HMBA provide a basis for the application of HMBA to clinical therapy of human cancers. Clinical trials with HMBA have been initiated.