Zhang Yuxiang, Dawson Marcia I, Ning Yangmin, Polin Lisa, Parchment Ralph E, Corbett Thomas, Mohamed Anwar N, Feng Kai-Chia, Farhana Lulu, Rishi Arun K, Hogge Donna, Leid Mark, Peterson Valerie J, Zhang Xiao-kun, Mohammad Ramzi, Lu Jing-Song, Willman Cheryl, VanBuren Eric, Biggar Sandra, Edelstein Mark, Eilender David, Fontana Joseph A
John D Dingell VA Medical Center, and Department of Medicine, Wayne State University, Detroit, MI 48201, USA.
Blood. 2003 Nov 15;102(10):3743-52. doi: 10.1182/blood-2003-01-0108. Epub 2003 Jul 31.
Acute myelogenous leukemia (AML) is a heterogeneous disease consisting of a variety of different leukemic subtypes. While acute promyelocytic leukemia displays marked sensitivity to the differentiating effects of trans-retinoic acid (tRA), other subtypes of AML display resistance. We now describe a novel compound (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) that induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1, and HL-60R, and in tRA-resistant patient leukemic blasts. The 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations that inhibit committed human bone marrow stem cell proliferation, that is, granulocyte/macrophage colony-forming units (CFU-GMs) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly(adenosine diphosphate) (poly(ADP)) ribose polymerase. While activation of the extracellular signal-regulated kinase (ERK) and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires c-Jun N-terminal kinase (JNK) activation. The 3-Cl-AHPC-mediated cleavage of the antiapoptotic B-cell leukemia XL (Bcl-XL) protein to a proapoptotic 18-kDa product is found in both the M07e cell line and patient leukemic blasts. The 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. While 3-Cl-AHPC does not activate retinoic nuclear receptors, it is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease.
急性髓系白血病（AML）是一种由多种不同白血病亚型组成的异质性疾病。虽然急性早幼粒细胞白血病对反式维甲酸（tRA）的分化作用表现出显著敏感性，但AML的其他亚型则表现出抗性。我们现在描述一种新型化合物（E）-4-[3-（1-金刚烷基）-4-羟基苯基]-3-氯肉桂酸（3-Cl-AHPC/MM002），它可诱导对tRA耐药的白血病细胞系M07e、KG-1和HL-60R以及对tRA耐药的患者白血病原始细胞凋亡。3-Cl-AHPC在抑制定向人类骨髓干细胞增殖（即粒细胞/巨噬细胞集落形成单位（CFU-GMs）仅30%）的浓度下完全抑制白血病集落形成。暴露于3-Cl-AHPC会导致半胱天冬酶激活和聚（二磷酸腺苷）（聚（ADP））核糖聚合酶的裂解。虽然细胞外信号调节激酶（ERK）和p38通路的激活对于3-Cl-AHPC介导的凋亡不是必需的，但最大程度的凋亡需要c-Jun氨基末端激酶（JNK）激活。在M07e细胞系和患者白血病原始细胞中均发现3-Cl-AHPC介导的抗凋亡B细胞白血病XL（Bcl-XL）蛋白裂解为促凋亡的18 kDa产物。用AML 1498细胞系接种的小鼠经3-Cl-AHPC治疗后，白血病原始细胞减少了3.3个对数级。虽然3-Cl-AHPC不激活视黄酸核受体，但它是AML细胞凋亡的有效诱导剂，可能代表了治疗这种疾病的一种新疗法。
