Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 75-82 ◽  
Author(s):  
JY Zhou ◽  
AW Norman ◽  
M Akashi ◽  
DL Chen ◽  
MR Uskokovic ◽  
...  
Keyword(s):  
Vitamin D3 ◽  
Calcium Metabolism ◽  
Calcium Absorption ◽  
Leukemic Cells ◽  
Inhibition Of Proliferation ◽  
Myc Oncogene ◽  
Differentiation And Proliferation ◽  
Bone Abnormalities

We describe several novel analogs of the seco-steroid 1,25(OH)2-vitamin D3[1,25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2–16ene-23yne-26,27F6- vitamin D3 is the most potent analog reported to date, having about 80- fold more activity than the reference 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also, this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly, intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2–16ene-23yne- 26,27F6-D3 was found to be markedly (15-fold) less than that of 1,25(OH)2D3. In addition, 1 alpha-25(OH)2D3 bound to 1,25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha- 25(OH)2–16ene-23yne-26,27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic, skin, and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.

scholarly journals Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 75-82 ◽  
Author(s):  
JY Zhou ◽  
AW Norman ◽  
M Akashi ◽  
DL Chen ◽  
MR Uskokovic ◽  
...  
Keyword(s):  
Vitamin D3 ◽  
Calcium Metabolism ◽  
Calcium Absorption ◽  
Leukemic Cells ◽  
Inhibition Of Proliferation ◽  
Myc Oncogene ◽  
Differentiation And Proliferation ◽  
Bone Abnormalities

Abstract We describe several novel analogs of the seco-steroid 1,25(OH)2-vitamin D3[1,25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2–16ene-23yne-26,27F6- vitamin D3 is the most potent analog reported to date, having about 80- fold more activity than the reference 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also, this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly, intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2–16ene-23yne- 26,27F6-D3 was found to be markedly (15-fold) less than that of 1,25(OH)2D3. In addition, 1 alpha-25(OH)2D3 bound to 1,25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha- 25(OH)2–16ene-23yne-26,27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic, skin, and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.

Effects of casein phosphopeptides on calcium absorption and metabolism bioactivity in vitro and in vivo

2018 ◽  
Vol 9 (10) ◽  
pp. 5220-5229 ◽  
Author(s):  
Shengwei Sun ◽  
Fei Liu ◽  
Guo Liu ◽  
Jianyin Miao ◽  
Hang Xiao ◽  
...  
Keyword(s):  
Calcium Metabolism ◽  
Calcium Uptake ◽  
Calcium Absorption ◽  
Casein Phosphopeptides

CPP1, CPP2 and P5 promoted calcium uptake in Caco-2 cells and affected isotopic calcium metabolism in rats.

Clinical Trial of Paricalcitol in Myelodysplastic Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4720-4720
Author(s):  
H. Phillip Koeffler ◽  
James O’Kelly ◽  
Noune Aslanian ◽  
Keyword(s):  
Clinical Trial ◽  
Myelodysplastic Syndrome ◽  
Clinical Response ◽  
Vitamin D3 ◽  
Single Agent ◽  
White Blood Cells ◽  
The Elderly ◽  
Leukemic Cells

Abstract Myelodysplastic syndrome is often a pernicious disorder associated with pancytopenia in the elderly. Therapeutic approaches need to balance their toxicities versus the side-effects of the disease. 1,25(OH)2-vitamin-D3 inhibits proliferation and induces differentiation of leukemic cells in vitro. Small clinical trials have shown slight efficacy in MDS. Hypercalcemia prevents the administration of doses of this seco-steroid, which have been shown to be effective in vitro. This has provided a stimulus to identify vitamin D analogs that have anti-leukemic activity with minimal hypercalcemic effects. Paricalcitol (19-nor-1,25(OH)2D2, Zemplar) has been approved by the FDA for the treatment of secondary hyperparathyroidism; the drug is unique because it has little hypercalcemic potential; but in vitro, it has strong antileukemic effects. We conducted a clinical trial of oral paricalcitol to twelve MDS patients whose disease varied between an IPSS of low to high. Therapy began at 8 μg per day and increased at two week intervals until serum calcium was slightly above normal level; at which point, dose was decreased by 4-8 μg qd. The amount of paricalcitol taken varied between 8 μg qod to 54 μg qd (average 16 μg qd). We confirmed that the drug was having biologic activity in vivo by examining a target of the activated vitamin D3 receptor, 1,25-(OH)2-vitamin-D3-24(OH)ase mRNA. Each patient had prominent induction of this transcript in his or her white blood cells. Furthermore, in selected patients serum paricalcitol was measured and confirmed to be prominently present. The drug was well tolerated in all patients. Two of the 12 patients showed a clinical response. One patient’s platelet counts rose from 50,000 to 120,000/ul blood over 5 weeks; however, the patient succumbed to a fatal fungal infection. The second patient responded by a decrease in RBC transfusions associated with a rise in his hemoglobin, which lasted for about 5 months. Eventually, his hemoglobin began to fall, and erythropoietin therapy was substituted for paricalcitol. In summary, high doses of paricalcitol were well tolerated in all patients. Two patients had a partial clinical response. In general, paricalcitol given as a single agent to individuals with MDS is not therapeutically very efficacious; further trials should examine it in combination with other approaches.

scholarly journals Therapeutic effects of sesamolin on leukemia induced by WEHI-3B in model mice

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Senthil Nagarajan ◽  
Jae Kwon Lee
Keyword(s):  
Nk Cell ◽  
Neoplastic Cell ◽  
Positive Control ◽  
Cytolytic Activity ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Control Drug ◽  
Lysis Activity

AbstractSesamolin is one of the lignans derived from sesame oil. It has demonstrated significant antioxidant, anti-aging, and anti-mutagenic properties. It also reportedly augments natural killer (NK) cell lysis activity. We previously reported that sesamolin also exerts anticancer effects in vitro and induces enhanced NK cell cytolytic activity against tumor cells. Herein, we aimed to determine the mechanism by which sesamolin prevents and retards tumorigenesis in BALB/c mouse models of leukemia induced by murine (BALB/c) myelomonocytic leukemia WEHI-3B cells. Banded neutrophils, myeloblasts, and monocytic leukemic cells were more abundant in the leukemia model than in normal mice. Sesamolin decreased the number of leukemic cells by almost 60% in the leukemia model mice in vivo; additionally, sesamolin and the positive control drug, vinblastine, similarly hindered neoplastic cell proliferation. Spleen samples were ~ 4.5-fold heavier in leukemic mice than those obtained from normal mice, whereas spleen samples obtained from leukemic mice treated with sesamolin had a similar weight to those of normal mice. Moreover, sesamolin induced a twofold increase in the cytotoxic activity of leukemic mouse NK cells against WEHI-3B cells. These results indicated that sesamolin exerts anti-leukemic effects in vivo.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2862-2864 ◽  
Author(s):  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Fabien Zassadowski ◽  
Nicole Balitrand ◽  
Isabelle Guillemot ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Acid Sensitivity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-transretinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P = .01) and lower relapse rate (P = .04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.

Differentiation arrest and stromal cell-independent growth of murine erythroleukemia cells are associated with elevated expression of ets-related genes but not with mutation of p53

1993 ◽  
Vol 13 (9) ◽  
pp. 5582-5592
Author(s):  
R J Nibbs ◽  
K Itoh ◽  
W Ostertag ◽  
P R Harrison
Keyword(s):  
Stromal Cells ◽  
Stromal Cell ◽  
Gene Activation ◽  
Leukemic Cells ◽  
Term Survival ◽  
Elevated Expression ◽  
D Cells ◽  
Murine Erythroleukemia

The ELM erythroleukemia is novel in that long-term survival of leukemic cells in culture (ELM-D cells) is dependent on contact with a bone marrow-derived stromal feeder cell layer. However, a number of stroma-independent (ELM-I) mutants that vary in their ability to differentiate in vitro in response to erythropoietin and interleukin-3 have been derived. We have attempted to define the genetic changes responsible for these different phenotypes. At the p53 locus in the primary leukemic cells, one copy of the gene has been lost whereas the other contains an 18-bp depletion, implicating its mutation as an early step in the development of the leukemia. Changes in ets gene expression have also been found. The Fli-1 gene region is rearranged in the primary tumor because of the insertion of a retrovirus inserted upstream of one Fli-1 allele, but this does not result in Fli-1 gene activation in any of the ELM-D or ELM-I cell lines except one. It seems significant that this line is the only one to have lost the ability to differentiate in response to erythropoietin. In addition, up-regulation of erg is associated with stromal cell-independent growth, since all ELM-I mutants have moderate levels of erg mRNA, whereas only low or undetectable levels are found in primary leukemic cells in vivo or in ELM-D cells in vitro. This up-regulation of erg mRNA seems to be important for stromal cell-independent growth, since ELM-D cells show elevated expression of the erg gene after separation from stromal cells. This seems to be made permanent in ELM-I mutants, since they do not down-regulate erg mRNA when grown in contact with stromal cells. We therefore propose that ets family members regulate both the survival and differentiation of erythroid cells.

Sign in / Sign up

Export Citation Format

Share Document