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Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro
M Kizaki1, M I Dawson, R Heyman
1Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
Abstract:
The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL-60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.
Insights
New synthetic retinoids targeting retinoic acid receptors (RARs) and retinoid X receptors (RXRs) show promise for treating leukemia. Compounds activating both RAR/RXR heterodimers and RXR homodimers effectively induce differentiation in leukemic cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Retinoids, including all-trans-retinoic acid (ATRA), influence hematopoietic cell proliferation and differentiation.
- These effects are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which form homodimers and heterodimers to regulate gene transcription.
Purpose of the Study:
- To develop novel synthetic retinoids with selective activity against RXR/RXR homodimers and RAR/RXR heterodimers.
- To evaluate the efficacy of these novel retinoids in inhibiting leukemic cell growth and inducing differentiation.
Main Methods:
- Synthesis of novel retinoid analogs targeting specific RXR and RAR receptor complexes.
- Assay of retinoid activity on leukemic cell lines (HL-60) and primary acute myeloid leukemia (AML) cells.
- Evaluation of synergistic effects when combining novel retinoids with ATRA.
Main Results:
- RXR-selective analogs (SR11236, SR11246) showed limited efficacy in inhibiting leukemic cell growth and inducing differentiation.
- Retinoids activating both RAR/RXR heterodimers and RXR homodimers (SR11249, SR11256, LGD1069) effectively inhibited proliferation and induced differentiation in HL-60 and primary AML cells, including APL.
- Combinations of ATRA with SR11249, SR11256, or LGD1069 demonstrated synergistic differentiation effects on HL-60 cells.
Conclusions:
- The RAR/RXR pathway is crucial for regulating proliferation and differentiation in acute myeloid leukemia cells.
- Synthetic retinoids targeting both RAR/RXR heterodimers and RXR homodimers hold therapeutic potential for AML.
- Combined retinoid therapy may enhance ATRA's differentiation activity, offering clinical benefits in specific leukemia contexts.