The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines.
The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines.
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DOI：
10.1182/blood-2002-02-0567
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发表时间：
2002-11
期刊：
影响因子：
20.3
通讯作者：
A. Batova;L. Shao;M. Diccianni;A. Yu;Tetsuya Tanaka;A. Rephaeli;A. Nudelman;John Yu
中科院分区：
文献类型：
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作者：
A. Batova;L. Shao;M. Diccianni;A. Yu;Tetsuya Tanaka;A. Rephaeli;A. Nudelman;John Yu
新戊酰氧基丁酸甲酯（AN-9）是一种组蛋白去乙酰化酶抑制剂，是丁酸的新型前药，作为一种有效且相对无毒的实体瘤抗癌剂，具有很大的前景。然而，很少有人知道它对造血系统恶性肿瘤的影响。在这项研究中，我们发现21例急性白血病的原始样本对AN-9的抗增殖作用敏感，50%抑制浓度（IC（50））为45.8 +/- 4.1 μ M。在集落形成试验中，原代T细胞急性淋巴细胞白血病（T-ALL）细胞对AN-9的敏感性是正常造血祖细胞、红系爆发形成单位和粒细胞/单核细胞集落形成单位的3倍。AN-9诱导T-ALL细胞系CEM的凋亡。癌症的一个常见问题是耐药性，这通常是复发性癌症的典型特征。值得注意的是，诊断时的T-ALL样本和复发时的急性髓性白血病样本在体外对多柔比星耐药，对AN-9敏感，两种样本的IC（50）均为50 μ M。更令人惊讶的是，2例t（4;11）ALL患儿在诊断和复发时获得的样本对AN-9最敏感，IC（50）值分别为25 μ M和17 μ M。此外，通过转染MDR-1基因获得的HL 60的阿霉素抗性克隆，HL 60/ADR，与亲本细胞一样对AN-9细胞毒性敏感。AN-9在伴有11 q23重排的婴儿白血病样本中诱导p21表达，但在T或B前体ALL中不诱导。总的来说，我们的研究结果表明，AN-9是一种选择性药物的造血系统恶性肿瘤，可以规避机制的耐药性限制最传统的化疗。
The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy.