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 language | English (US) |
---|---|
Pages (from-to) | 301-313 |
Number of pages | 13 |
Journal | Leukemia Research |
Volume | 31 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2007 |
Externally published | Yes |
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