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Oncotarget Jun 2016Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently...
Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with Cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted.
Topics: Abietanes; Adult; Aged; Aged, 80 and over; Apoptosis; Bcl-2-Like Protein 11; Cytarabine; Drug Synergism; Ergocalciferols; Female; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; RNA Interference; Receptors, Calcitriol; Tumor Cells, Cultured; U937 Cells
PubMed: 27144333
DOI: 10.18632/oncotarget.8998 -
Mechanisms of Development Oct 2018Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and...
Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and manipulated are areas of intense interest. Nutrient signaling plays an important role in pattern formation during regeneration. Retinoic acid signaling is the most characterized pathway during this process. Exogenous retinoic acid (RA) reprograms the pattern information in regenerating cells to a more posterior, ventral, and proximal identity. Vitamin D signaling shares several molecular similarities with RA and has been shown to alter pattern formation during zebrafish pectoral fin regeneration. To determine if exogenous Vitamin D signaling is capable of reprograming pattern in the axolotl limb blastema, we treated regenerating limbs with a potent Vitamin D agonist. Under the studied conditions, exogenous Vitamin D did not act in a manner similar to RA and failed to proximalize the pattern of the resulting regenerates. The Vitamin D treatment did result in several skeletal defects during regeneration, including carpal fusions along the A/P axis; failure to integrate the newly regenerated tissue with the existing tissue, formation of ectopic nodules of cartilage at the site of amputation, and altered bone morphology in uninjured skeletal tissue.
Topics: Ambystoma mexicanum; Amputation, Surgical; Animals; Body Patterning; Bone and Bones; Cell Differentiation; Ergocalciferols; Extremities; Organogenesis; Phenotype; Regeneration; Signal Transduction; Vitamin D
PubMed: 30096415
DOI: 10.1016/j.mod.2018.08.004 -
Journal of Oral Microbiology 2024is a virulent microorganism associated with dental caries. This study aimed to investigate the antimicrobial effects of Cholecalciferol (D3) and Doxercalciferol (D2),...
BACKGROUND
is a virulent microorganism associated with dental caries. This study aimed to investigate the antimicrobial effects of Cholecalciferol (D3) and Doxercalciferol (D2), against and on glycosyltransferase gene expression.
METHODS
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of D3 and D2 for were determined according to the Clinical Laboratory Standards Institute guidelines. The effect of the compounds on environmental pH in 1% w/v and 5% w/v sucrose broth cultures after 24 hours were assessed colorimetrically. Additionally, their impact on glycosyltransferases gene expression () in 5% w/v sucrose culture was evaluated using quantitative real-time PCR.
RESULTS
The MBCs of D3 and D2 were 83 µg/ml and 166 µg/ml respectively. Both compounds were effective in preventing the local pH drop <5.5 at ≥166 µg/ml in sucrose supplemented cultures. However, the compounds did not inhibit pH drop at MIC values. Notably, D2 upregulated expression significantly ( < 0.05) and downregulated and .
CONCLUSION
Vitamin D2 and D3 inhibited mediated pH drop in sucrose supplemented cultures and altered glycosyltransferase expression, suggesting potential therapeutic roles in dental caries prevention. Further research is needed to assess their full impact on survival under environmental stresses.
PubMed: 38550660
DOI: 10.1080/20002297.2024.2327758 -
The Journal of Steroid Biochemistry and... Oct 2017Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its...
Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its derivatives (VDDs) effectively to the clinic, we developed a two-pronged approach. First, by adding the plant-derived Carnosic Acid (CA) to a vitamin D2 derivative Doxercalciferol we increased its differentiation potency without increasing it hypercalcemic properties. Second, we added these two agents together to AML cells already treated with Cytarabine (AraC), the standard drug for the treatment of patients with AML. We now report that BRAF, a part of the MAPK signaling pathway, is required for the optimally increased cell death in this system and acts upstream of BIM, the regulator of the caspase cascade that leads to cell death by apoptosis. It is proposed that this therapeutic regimen should be tested in a clinical trial.
Topics: Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Cytarabine; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins B-raf; Signal Transduction; Vitamin D
PubMed: 27637326
DOI: 10.1016/j.jsbmb.2016.09.009 -
The Journal of Steroid Biochemistry and... Nov 2016Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself....
Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself. There is an emerging realization that the therapeutic outcomes may be improved by combining AraC with other compounds. Here we report that the addition of a differentiating agent combination immediately following AraC damage to AML blasts, selectively increases the cell kill. The experiments were performed using cultured cells from established cell lines of AML (HL60 and U937). The cells were exposed to 100nM AraC, a concentration which produced approximately 25-50% cell kill, followed by a combination of 100nM 1alpha-hydroxyvitamin D2 (1-D2) and 10μM carnosic acid (CA), which together can serve as a powerful differentiating agent combination for AML cells, but are not toxic alone. AraC-induced cell death, measured by annexin V/propidium iodide, was significantly (p<0.01) increased by the 1-D2/CA combination in both cell lines, but not by 1-D2 or CA alone. The enhancement of cell death occurred by both apoptosis and necrosis, was associated with increased DNA damage and with higher levels of DNA damage response (DDR) activated marker Chk1, but the expression of p27, a cell cycle inhibitor protein, was not enhanced by 1-D2/CA. The principal finding is that a vitamin D analog 1-D2 combined with a plant-derived antioxidant CA can markedly augment the cytotoxic action of AraC, an anti-leukemia therapeutic agent.
Topics: Abietanes; Annexin A5; Antimetabolites, Antineoplastic; Antioxidants; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Differentiation; Comet Assay; Cytarabine; DNA Damage; Ergocalciferols; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Phosphorylation; Propidium; U937 Cells
PubMed: 26319201
DOI: 10.1016/j.jsbmb.2015.08.023