Komura Naoyuki, Ikeda Yoko, Masuda Natsuko, Umezawa Yoji, Ito Keisuke, Kizaki Masahiro, Umezawa Kazuo
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan.
Leuk Res. 2007 Mar;31(3):301-13. doi: 10.1016/j.leukres.2006.07.015. Epub 2006 Sep 11.
All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. UF-1 cells were established from an ATRA-resistant APL patient, and were previously shown to possess a single amino acid (or nucleotide) substitution, Arg276Trp, in their ATRA receptor. In the present research, we designed several ATRA derivatives having a hydrophobic alkyl ketone moiety instead of the negatively charged carboxylic acid moiety. Among them the ethyl ketone derivative, Et-ketone ATRA, was shown to induce the differentiation of UF-1 cells when assessed in terms of intracellular ROS production. It also induced the formation of PML NBs and expression of CD11b antigen marker and p21, transcriptional targets of RARalpha. Et-ketone ATRA did not induce these phenotypic changes in wild-type APL NB4 cells. Furthermore, we found that Et-ketone ATRA induced apoptosis selectively in UF-1 cells, i.e., not in other leukemic cells. The induction of apoptosis was shown to be partly due to the up-regulation of Bax protein. Thus, Et-ketone ATRA selectively induced differentiation and apoptosis in ATRA-resistant APL UF-1 cells, and is likely to be useful for the clinical treatment of the Arg276Trp-type of ATRA-resistant APL.
全反式维甲酸（ATRA）可诱导急性早幼粒细胞白血病（APL）细胞分化为中性粒细胞。UF-1细胞源自一名对ATRA耐药的APL患者，先前研究表明其维甲酸受体存在单个氨基酸（或核苷酸）取代，即Arg276Trp。在本研究中，我们设计了几种具有疏水烷基酮部分而非带负电荷羧酸部分的ATRA衍生物。其中，乙基酮衍生物Et-酮ATRA在根据细胞内活性氧生成进行评估时，显示可诱导UF-1细胞分化。它还诱导了早幼粒细胞白血病蛋白（PML）核小体的形成以及CD11b抗原标志物和p21（维甲酸受体α的转录靶点）的表达。Et-酮ATRA在野生型APL NB4细胞中未诱导这些表型变化。此外，我们发现Et-酮ATRA仅在UF-1细胞中选择性诱导凋亡，即在其他白血病细胞中不会诱导凋亡。凋亡诱导部分归因于Bax蛋白的上调。因此，Et-酮ATRA在对ATRA耐药的APL UF-1细胞中选择性诱导分化和凋亡，可能对Arg276Trp型对ATRA耐药的APL临床治疗有用。
