Hsu C A, Rishi A K, Su-Li X, Gerald T M, Dawson M I, Schiffer C, Reichert U, Shroot B, Poirier G G, Fontana J A
Department of Medicine and Cancer Center, University of Maryland at Baltimore and the Baltimore VA Medical Center, USA.
Blood. 1997 Jun 15;89(12):4470-9.
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.
全反式维甲酸（RA）已被证明是治疗急性早幼粒细胞白血病的一种有效治疗药物。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具有抗性。在本报告中，我们描述了一种新型类维生素A 6-[3-(1-金刚烷基)-4-羟基苯基]-2-萘甲酸（AHPN；CD437），它不仅能完全抑制对RA耐药的白血病细胞系HL-60R和K562的增殖，还能诱导这些细胞凋亡。HL-60R细胞暴露于CD437会导致细胞周期蛋白依赖性激酶抑制剂p21(waf1/cip1)以及GADD45 mRNA迅速（在30分钟内）增加。CD437介导的程序性细胞死亡在2小时内即可显现，这可通过CPP32蛋白酶的切割和激活以及聚（ADP-核糖）聚合酶的切割来表明。随后是bcl-2的切割和核小体间DNA降解。HL-60R细胞不表达类维生素A核受体RARβ和RARγ，而是表达截短的RARα。因此，CD437诱导p21(waf1/cip1)和GADD45 mRNA以及凋亡是通过一种不涉及类维生素A核受体的独特机制发生的。CD437代表一种在治疗髓性白血病方面具有治疗潜力的独特类维生素A。
