Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway
Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway
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DOI：
10.1182/blood.v89.12.4470
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发表时间：
1997-06-15
期刊：
影响因子：
20.3
通讯作者：
Fontana, JA
中科院分区：
文献类型：
--
作者：
Hsu, CA;Rishi, AK;Fontana, JA
反式维甲酸（RA）已被证明是治疗急性早幼粒细胞白血病的有效药物。不幸的是，急性髓性白血病的其他亚型对RA的抗增殖和分化作用有抵抗性。在本报告中，我们描述了一种新的类维甲酸6-[3-（1-金刚烷基）-4-羟基苯基]-2-萘羧酸（AHPN; CD437），它不仅完全抑制RA抵抗白血病细胞系HL-60R和K562的增殖，而且还诱导这些细胞凋亡。HL-60R暴露于CD437导致细胞周期蛋白依赖性激酶抑制剂p21（waf1/cip1）和GADD45 mRNA的快速（30分钟内）增加，CD437介导的程序性细胞死亡的表现在2小时内被注意到，这是由CPP32蛋白酶的裂解和激活以及聚（adp核糖）聚合酶的裂解所表明的。随后是bcl-2的裂解和核小体间DNA的降解。HL-60R细胞不表达类视黄醛核受体RAR β和RAR γ，表达截断的RAR α。因此，CD437诱导p21（waf1/cip1）和GADD45 mrna和细胞凋亡是通过一种独特的机制发生的，不涉及类视黄醇核受体。CD437代表了一种独特的类维生素a，在治疗髓性白血病方面具有治疗潜力。(C) 1997年由美国血液病学会出版。
Trans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA, In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21(waf1/cip1) as well as GADD45 mRNA, Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RAR beta and RAR gamma and express a truncated RAR alpha. Thus, CD437 induction of p21(waf1/cip1) and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia. (C) 1997 by The American Society of Hematology.