Designed ATRA analogue active against ATRA-resistant acute promyelocytic leukemia cells having a single nucleotide substitution in their retinoic acid receptor.
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.
Komura
Naoyuki
N
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan.
Ikeda
Yoko
Y
Masuda
Natsuko
N
Umezawa
Yoji
Y
Ito
Keisuke
K
Kizaki
Masahiro
M
Umezawa
Kazuo
K
D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000096:biosynthesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015316:Genetic Therapy / Q000379:methods; D018922:HL-60 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017354:Point Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000187:drug effects
C494826:BAX protein, human; D039481:CD11b Antigen; D050759:Cyclin-Dependent Kinase Inhibitor p21; C509295:ITGAM protein, human; C000607071:RARA protein, human; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D051028:bcl-2-Associated X Protein; D014212:Tretinoin