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

Naoyuki Komura, Yoko Ikeda, Natsuko Masuda, Yoji Umezawa, Keisuke Ito, Masahiro Kizaki, Kazuo Umezawa

Research output: Contribution to journalArticle

6 Scopus citations

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 RARα. 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.

Original languageEnglish (US)
Pages (from-to)301-313
Number of pages13
JournalLeukemia Research
Volume31
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • ATRA resistance
  • Acute promyelocytic leukemia (APL)
  • All-trans retinoic acid (ATRA)
  • Apoptosis
  • Differentiation
  • Et-ketone ATRA
  • Molecular design

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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