Designed ATRA analogue active against ATRA-resistant acute promyelocytic leukemia cells having a single nucleotide substitution in their retinoic acid receptor.

Abstract

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.

• Authors: Naoyuki Komura, Yoko Ikeda, Natsuko Masuda, Yoji Umezawa, Keisuke Ito, Masahiro Kizaki, Kazuo Umezawa
• Journal: Leukemia research (Leuk Res) Vol. 31 Issue 3 Pg. 301-13 (Mar 2007) ISSN: 0145-2126 [Print] England
• PMID: 16968653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAX protein, human
• CD11b Antigen
• Cyclin-Dependent Kinase Inhibitor p21
• ITGAM protein, human
• RARA protein, human
• Reactive Oxygen Species
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• bcl-2-Associated X Protein
• Tretinoin

Topics

• Apoptosis (drug effects)
• CD11b Antigen (biosynthesis, drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Genetic Therapy (methods)
• HL-60 Cells
• Humans
• Hydrophobic and Hydrophilic Interactions
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, pathology)
• Molecular Structure
• Oligonucleotide Array Sequence Analysis (methods)
• Point Mutation
• Reactive Oxygen Species (metabolism)
• Receptors, Retinoic Acid (drug effects, genetics)
• Retinoic Acid Receptor alpha
• Structure-Activity Relationship
• Tretinoin (analogs & derivatives, chemistry, pharmacology)
• bcl-2-Associated X Protein (biosynthesis, drug effects)