Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia
Abstract
:1. Overview of Nuclear Receptors
2. Potential Roles of NRs in Acute Myeloid Leukemia
3. Potential Roles of NRs in Chronic Myelogenous Leukemia
4. Conclusions and Perspectives
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Types of Leukemia | Subtypes | Cytogenetic Abnormalities | NR-Agonists Based Treatments | Cells/Patients | Effects | Ref. |
---|---|---|---|---|---|---|
AML | APL | PML-RAR-α, PLZF-RAR-α | ATRA | 24 APL patients | Induced complete remission without bone marrow hypoplasia | [35] |
ATRA | 346 APL patients | Improved disease-free and overall survival as compared with chemotherapy alone | [39] | |||
ATRA + ATO | 61 APL patients | Improved complete remission rates and disease-free survival | [45] | |||
ATRA + ATO + chemotherapy | 124 APL patients | Improved relapse-free and failure-free survival | [46,48] | |||
ATRA + ATO | 156 APL patients | Induced complete remission and improved 2-year event-free survival rates and overall survival | [47] | |||
ATRA + ATO | 276 APL patients | Induced complete remission and improved the event-free survival, cumulative incidence of relapse, and overall survival at 50 months | [49] | |||
PPAR-γ agonist + ATRA | ATRA-sensitive NB4 cells | Sensitized ATRA-induced effects, promoted apoptosis, and enhanced differentiation of NB4 cells | [55] | |||
ATRA-resistant NB4-derived subline MR2 cells | Partially reversed ATRA resistance in MR2 cells | |||||
Non-APL subtypes | Heterogeneous | ATRA | HL-60 cells | Induced apoptosis and differentiation | [54] | |
ATRA + chemotherapy | Patients with non-APL subtypes of AML | No significant clinical benefit in terms of overall survival or disease-free survival | [67] | |||
PPAR-γ agonist | HL-60, KG-1, Mono-MAC6, and THP-1 cells | Induced differentiation, promoted apoptosis, and suppressed proliferation, activated JNK and p38 MAPK pathways, inhibited ERK pathway, enhanced the production of reative oxygen species, and induced cell cycle arrest | [53,68] | |||
Primary cells from AML patients | [54,69,70,71,72] | |||||
PPAR-γ agonist (ODDO) | 5 patients with refractory/relapsed AML | No significant clinical benefit, except one patient showed decreased bone marrow blasts and monocytes | [72] | |||
PPAR-γ agonist + RXR agonist + ATRA | HL-60 cells | Synergistic anti-leukemic effects, promoted apoptosis and induced differentiation, suppressed ERK pathway, decreased the expression of anti-apoptotic Bcl-2, and increased the expression of pro-apoptotic Bax | [54] | |||
RXR agonist + LXR agonist | THP-1 cells | Induced differentiation and enhanced cytotoxicity | [73,74] | |||
Primary cells from AML patients | ||||||
RXR agonist (bexarotene) | 27 AML patients who either had refractory/relapsed diseases, or were not eligible for standard cytotoxic chemotherapy | Four (15%) patients showed reduced bone marrow blasts to less than 5%; 11 (41%) patients had improved platelet counts, 7 (26%) patients had improved neutrophil counts; and 3 patients with relapsed AML survived more than one year. | [75] | |||
VDR agonist + azacytidine (demethylating agent) | HL-60 and MOLM13 cells | Synergistic inhibition on leukemic cell proliferation | [82] | |||
VDR agonist + dimethyl fumarate (Nrf2 activator) | HL-60 cells | Synergistic pro-differentiating effects through cooperatively upregulating VDR and Nrf2 | [86] | |||
VDR agonist + GSK3 inhibitor | HL-60 and OCI-AML3 cells | Synergistic pro-differentiating effects through an increased cell cycle arrest in G0-G1 phase and a decreased expression of cyclin A, induced phosphorylation at Ser208 of VDR, enhanced VDR transcriptional activities, and activated JNK pathway | [87] | |||
CML | BCR-ABL | PPAR-γ agonist +TKIs | K562 | Decreased the clonogenic potential of CML cells through downregulating the expression of STAT5 and its target genes HIF2α and Cbp/p300-interacting transactivator 2 | [95] | |
Leukemia stem cell from CML patients | ||||||
PPAR-γ agonist (pioglitazone) + imatinib | 3 CML patients | Achieved sustained complete molecular remission, up to 4.7 years after the discontinuation of pioglitazone | [95] | |||
PPAR-γ agonist (pioglitazone) + imatinib | 24 CML patients | The cumulative incidence of molecular response 4.5 was 56% by 12 months, in comparison with 23% in the parallel control group with patients that only received imatinib | [97] | |||
PPAR-α agonist + imatinib | KCL22 cells | Synergistic anti-leukemic effects through upregulating hOCT1 gene expression and increasing the uptake of imatinib by CML cells | [103] | |||
Leukemia stem cell from CML patients |
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Pan, P.; Chen, X. Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia. Cells 2020, 9, 1921. https://doi.org/10.3390/cells9091921
Pan P, Chen X. Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia. Cells. 2020; 9(9):1921. https://doi.org/10.3390/cells9091921
Chicago/Turabian StylePan, Pan, and Xiao Chen. 2020. "Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia" Cells 9, no. 9: 1921. https://doi.org/10.3390/cells9091921