Vitamin D Derivatives in Acute Myeloid Leukemia: The Matter of Selecting the Right Targets

Marcinkowska, Ewa

doi:10.3390/nu14142851

Cited by 7 publications

(8 citation statements)

References 89 publications

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“…However, the results of small clinical trials with 1,25D against MDS or AML were inconclusive [ 26 ]. Now it seems obvious that 1,25D, or its low calcemic analogs, will not become sole treatment against hematological malignancies, but might be used in combination treatments [ 27 ]. The immuno-stimulating function of 1,25D in hematological malignancies, which are always accompanied by immune dysfunction, is of primary importance.…”

Section: Discussionmentioning

confidence: 99%

Immuno-Stimulating Activity of 1,25-Dihydroxyvitamin D in Blood Cells from Five Healthy People and in Blasts from Five Patients with Leukemias and Pre-Leukemic States

Marchwicka

Nowak

Satyr

et al. 2023

IJMS

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(1) Hematological malignancies are characterized by an immortalization, uncontrolled proliferation of blood cells and their differentiation block, followed by the loss of function. The primary goal in the treatment of leukemias is the elimination of rapidly proliferating leukemic cells (named blasts). However, chemotherapy, which removes proliferating blasts, also prevents the remaining immune cells from being activated. Acute leukemias affect elderly people, who are often not fit to survive aggressive chemotherapy. Therefore, there is a need of milder treatment, named differentiation therapy, which might simulate the immune system of the patient. 1,25-Dihydroxyvitamin D, or low-calcemic analogs of this compound, were proposed as supporting therapy in acute leukemias. (2) Bone marrow blasts from patients with hematological malignancies, and leukocytes from healthy volunteers were ex vivo exposed to 1,25-dihydroxyvitamin D, and then their genomes and transcriptomes were investigated. (3) Our analysis indicates that 1,25-dihydroxyvitamin D regulates in blood cells predominantly genes involved in immune response, such as CAMP (cathelicidin antimicrobial peptide), CP (ceruloplasmin), CXCL9 (C-X-C motif chemokine ligand 9), CD14 (CD14 molecule) or VMO1 (vitelline membrane outer layer 1 homolog). This concerns blood cells from healthy people, as well as blasts from patients with hematological malignancies. In addition, in one patient, 1,25-dihydroxyvitamin D significantly downregulated transcription of genes responsible for cell division and immortalization. (4) In conclusion, the data presented in this paper suggest that addition of 1,25-dihydroxyvitamin D to the currently available treatments would stimulate immune system, inhibit proliferation and reduce immortal potential of blasts.

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Section: Discussionmentioning

confidence: 99%

Immuno-Stimulating Activity of 1,25-Dihydroxyvitamin D in Blood Cells from Five Healthy People and in Blasts from Five Patients with Leukemias and Pre-Leukemic States

Marchwicka

Nowak

Satyr

et al. 2023

IJMS

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“…In 2021, a study by Lijun Wang et al, [19] further con rmed the correlation between certain allele genes at ve loci, namely HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1, and the occurrence of these diseases. Some of these genes are susceptibility genes, such as [20,21] .Currently, the main methods of treating celiac disease include a gluten-free diet, gliadin peptide enzyme inhibitors, and supplementation of vitamins and minerals. Additionally, an increasing amount of research has revealed the signi cant role that modulating the gut microbiota plays in celiac disease [22,23] .In addition, dysbiosis of the gut microbiota is also an important risk factor for the development of leukemia [24,25] .It is worth mentioning that celiac disease is an immune stress response of the small intestinal epithelium to gluten consumption.…”

Section: Discussionmentioning

confidence: 99%

Causal relationship between diet and celiac disease in leukemia: A two-sample Mendelian randomization study

cheng,

Zhang,

Luo

et al. 2023

Preprint

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Objective To explore the causal relationship between celiac disease and a wheat-free diet with leukemia. Methods We obtained genome-wide association study (GWAS) data on celiac disease, a wheat-free diet, and leukemia from published literature. Single nucleotide polymorphisms (SNPs) representing celiac disease or a wheat-free diet were selected as instrumental variables. Two-sample Mendelian randomization (MR) analyses were conducted using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. The reliability of the results was evaluated using MR-Egger test, MR-PRESSO test, Cochran Q test, and leave-one-out test. Results We identified 16 SNPs associated with celiac disease as instrumental variables and 5 SNPs associated with a wheat-free diet as instrumental variables. MR analysis showed that an increase in celiac disease is associated with an increased risk of leukemia (OR = 1.03, 95% CI: 1.01-1.07, P = 0.03) according to the IVW method, and similar results were obtained using the MR-Egger regression (OR = 1.04, 95% CI: 1.00-1.09, P = 0.04). Consistent causal effects were observed using the five methods. The IVW method revealed that a wheat-free diet in healthy individuals leads to an increased risk of leukemia (OR = 1.06, 95% CI: 1.03-1.08, P = 2.36E-05), and similar results were obtained using the MR-Egger regression (OR = 1.06, 95% CI: 0.98-1.15, P = 0.27). The five methods consistently supported these causal directions. Reliability analysis indicated no heterogeneity, no pleiotropy, and no significant bias in both sets of MR analyses, suggesting the reliability of the results. Conclusion Celiac disease is a risk factor for leukemia, and a wheat-free diet in healthy individuals also increases the risk of developing leukemia. Adjusting one's own immune system may be the best choice for individuals with celiac disease.

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“…The hormonal form of vitamins D 3 and D 2 , 1α,25-dihydroxyvitamin D 3 /D 2 (1,25D 3/2 ), is a well-known inducer of myeloid differentiation in various nonAPL AML cell types [9,10]. 1,25D 3 is the physiological ligand of the vitamin D receptor (VDR), a member of the nuclear receptor subfamily type II that includes retinoid X receptors (RXRs) and retinoic acid receptors.…”

Section: Introductionmentioning

confidence: 99%

Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells

Jramne-Saleem,

Danilenko

2024

IJMS

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Active vitamin D derivatives (VDDs)—1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs—are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.

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Vitamin D Derivatives in Acute Myeloid Leukemia: The Matter of Selecting the Right Targets

Cited by 7 publications

References 89 publications

Immuno-Stimulating Activity of 1,25-Dihydroxyvitamin D in Blood Cells from Five Healthy People and in Blasts from Five Patients with Leukemias and Pre-Leukemic States

Immuno-Stimulating Activity of 1,25-Dihydroxyvitamin D in Blood Cells from Five Healthy People and in Blasts from Five Patients with Leukemias and Pre-Leukemic States

Causal relationship between diet and celiac disease in leukemia: A two-sample Mendelian randomization study

Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells

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