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Anticancer Research 2005Transitional cell carcinoma (TCC) in dogs is associated with high morbidity and mortality. Calcitriol and its analog seocalcitol, combined with medium-chain triglyceride...
BACKGROUND
Transitional cell carcinoma (TCC) in dogs is associated with high morbidity and mortality. Calcitriol and its analog seocalcitol, combined with medium-chain triglyceride (MCT), have potential for the treatment of this disease.
MATERIALS AND METHODS
TCC cells were treated with calcitriol or seocalcitol, alone or combined with MCT. Cell growth, cell cycle kinetics, vitamin D receptor (VDR) localization and expression, and Bcl-2 expression were measured.
RESULTS
Canine TCC expresses high levels of nuclear VDR. Furthermore, calcitriol and seocalcitol significantly inhibited cell growth and calcitriol caused G0/G1 cell cycle arrest. Bcl-2 expression was slightly decreased in cells treated with these compounds, although no significant changes in VDR expression were observed. MCT enhanced the growth inhibitory effect of both compounds.
CONCLUSION
Calcitriol and seocalcitol inhibited TCC cell growth via induction of cell cycle arrest and MCT enhanced this effect. Therefore, calcitriol and seocalcitol with MCT may have therapeutic potential for canine bladder cancer.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Calcitriol; Carcinoma, Transitional Cell; Cell Cycle; Cell Growth Processes; Dog Diseases; Dogs; Proto-Oncogene Proteins c-bcl-2; Receptors, Calcitriol; Triglycerides; Urinary Bladder Neoplasms
PubMed: 16080513
DOI: No ID Found -
Nutrition & Metabolism 2018Liver dysfunction is a topic of global concern with many advancing therapies being researched. Though vitamin D takes a center place, other therapies especially... (Review)
Review
BACKGROUND
Liver dysfunction is a topic of global concern with many advancing therapies being researched. Though vitamin D takes a center place, other therapies especially nutritional are also gaining ground. Vitamin D has gone beyond its role in skeletal disorders by showcasing its associations in other metabolic dysfunctions too.
RESULT
Epidemiological evidences show a correlation between the status of vitamin D and different forms of cancer. Vitamin D receptors and alterations in gene expression appear decisive in the development of chronic liver disorders. Nutritional status therefore plays a significant role in avoiding the complications related to liver dysfunctions, making it mandatory in maintaining vitamin D sufficiency in the body. Therapies with omega-3 fatty acids, antioxidants, amino acids, steroids also render benefits which could be further explored. Recent research on the progression of certain forms of liver cancer using vitamin D analogs like Seocalcitol EB 1089 has shown good promise.
CONCLUSION
The anti-inflammatory and immuno- regulatory properties of vitamin D makes its analogs, suitable candidates of better choice for the prevention and treatment of liver disorders and cancer.
PubMed: 29449867
DOI: 10.1186/s12986-018-0251-5 -
FN1 overexpression is correlated with unfavorable prognosis and immune infiltrates in breast cancer.Frontiers in Genetics 2022To investigate the correlation of fibronectin 1 (FN1) expression with prognosis and tumor-infiltrating immune cells in breast cancer (BRCA). FN1 mRNA and protein...
To investigate the correlation of fibronectin 1 (FN1) expression with prognosis and tumor-infiltrating immune cells in breast cancer (BRCA). FN1 mRNA and protein expressions were analyzed through Tumor Immune Estimation Resource (TIMER), Gene Set Cancer Analysis (GSCA), Human Protein Atlas (HPA) databases, and immunohistochemical analysis. The clinicopathological characteristics and genetic factors affecting the FN1 mRNA expression were assessed by various public databases. Then, we analyzed the prognostic value of FN1 in BRCA by Kaplan-Meier plotter, receiver operating characteristic, and Cox regression analyses. Further, the UCSC Xena database was used to retrieve TCGA-BRCA expression profiles for functional enrichment analysis and immune cell infiltration analysis. The potential drugs for the BRCA patients with high- FN1 expression were identified using the connectivity map analysis. FN1 was upregulated in BRCA tissues compared with normal tissues. High FN1 mRNA expression was correlated with poor clinical outcomes and had good performance in predicting the survival status of BRCA patients. Further, Cox regression analysis showed that FN1 was an independent prognostic factor for predicting the overall survival of patients with BRCA. Moreover, hypermethylation of FN1 contributed to a better prognosis for BRCA patients. Functional enrichment analyses revealed the ECM-receptor interaction pathway and focal adhesion as the common pathways. Moreover, FN1 showed a significant association with tumor-infiltrating immune cells and immune checkpoint inhibitors. Several drugs such as telmisartan, malotilate, and seocalcitol may have therapeutic effects in BRCA patients with high FN1 expression. FN1 might serve as a novel prognostic biomarker and a novel therapeutic target for BRCA. Besides, the association of FN1 with immune cells and immune checkpoint inhibitors may provide assistance for BRCA treatment.
PubMed: 36035176
DOI: 10.3389/fgene.2022.913659 -
Journal of Leukocyte Biology Apr 2013Epigenetics contributes to the development of variety of diseases by modulation of gene expression. We evaluated the effect of HIV-induced VDR methylation on loss of...
Epigenetics contributes to the development of variety of diseases by modulation of gene expression. We evaluated the effect of HIV-induced VDR methylation on loss of TCs. HIV/TC displayed enhanced VDR-CpG methylation and increased expression of Dnmt3b but attenuated expression of VDR. A demethylating agent, AZA, inhibited this effect of HIV. HIV/TC also displayed the activation of the RAS, which was reversed by EB (a VDA). Further, HIV/TCs displayed enhanced generation of ROS and induction of DSBs but attenuated DNA repair response. However, in the presence of AZA, EB, LOS (a RAS blocker), Cat, and tempol (free radical scavengers), HIV-induced TC ROS generation and induction of DSBs were attenuated but associated with enhanced DNA repair. Additionally, AZA, EB, and LOS provided protection against HIV-induced TC apoptosis. These findings suggested that HIV-induced TC apoptosis was mediated through ROS generation in response to HIV-induced VDR methylation and associated activation of the RAS.
Topics: Angiotensin II Type 1 Receptor Blockers; Antimetabolites, Antineoplastic; Apoptosis; Azacitidine; Calcitriol; Catalase; Cells, Cultured; CpG Islands; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Repair; Enzyme Inhibitors; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; HIV-1; Humans; Losartan; Lymphocyte Count; Reactive Oxygen Species; Receptors, Calcitriol; T-Lymphocytes; ras Proteins; DNA Methyltransferase 3B
PubMed: 23390308
DOI: 10.1189/jlb.0812383 -
British Journal of Cancer Jul 2003Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most... (Clinical Trial)
Clinical Trial
Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Calcitriol; Carcinoma, Hepatocellular; Disease Progression; Female; Humans; Liver Neoplasms; Male; Middle Aged; Receptors, Calcitriol; Treatment Outcome
PubMed: 12865912
DOI: 10.1038/sj.bjc.6601104 -
Agri : Agri (Algoloji) Dernegi'nin... Oct 2022The aim of this study is to investigate the effect of vitamin D on pain threshold in rats. In addition, to examine, whether EB1089, which is a vitamin D receptor...
OBJECTIVES
The aim of this study is to investigate the effect of vitamin D on pain threshold in rats. In addition, to examine, whether EB1089, which is a vitamin D receptor agonist, can contribute to this mechanism by increasing the effects of the receptor.
METHODS
In the study, 24 male Wistar Albino rats of 3 months, an average of 240-260 g, were used. The animals were randomly divided into three groups, eight animals in each group. Groups; control, vitamin D (10 µg/kg), and EB1089 (10 µg/kg). Tail flick and hot plate tests were used to evaluate the antinociceptive effect. Measurements were taken at 0 min before drug administration and at 30, 60, and 90 min after drug administration and times were recorded in seconds. Serotonin levels were also analyzed by ELISA method in plasma obtained from intracardiac blood samples taken at the end of the experiment.
RESULTS
Vitamin D and EB1089 significantly increased the time to endure pain in the tail flick test compared to the control group (p<0.05). In the hot plate test, EB1089 group significantly extended the pain threshold compared to the control group (p<0.05), while the vitamin D group did not create a significant difference, although it had a higher latency than the control group (p>0.05). There was no significant difference between the groups in terms of serotonin levels (p>0.05).
CONCLUSION
As a result of our study, the administration of vitamin D and EB1089 increased the pain threshold in animals and increased pain resistance.
Topics: Animals; Male; Rats; Analgesics; Pain; Rats, Wistar; Receptors, Calcitriol; Serotonin; Vitamin D
PubMed: 36300743
DOI: 10.14744/agri.2022.60590 -
British Journal of Cancer Mar 2002Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol... (Clinical Trial)
Clinical Trial
Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Calcitriol; Carcinoma; Disease Progression; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 11875725
DOI: 10.1038/sj.bjc.6600162 -
Scientific Reports Jul 2020Infections with the mosquito-transmitted dengue virus (DENV) are a pressing public health problem in many parts of the world. The recently released commercial vaccine...
Infections with the mosquito-transmitted dengue virus (DENV) are a pressing public health problem in many parts of the world. The recently released commercial vaccine for DENV has encountered some problems, and there is still no effective drug to treat infections. Vitamin D has a well characterized role in calcium and phosphorus homeostasis, but additionally has a role in the immune response to bacterial and viral pathogens. In this study a number of fused bicyclic derivatives of 1H-pyrrolo[1,2]imidazol-1-one with vitamin D receptor (VDR) agonist activity were evaluated for possible anti-DENV activity. The results showed that five of the compounds were able to significantly inhibit DENV infection. The most effective compound, ZD-3, had an EC value of 7.47 μM and a selective index of 52.75. The compounds were only effective when used as a post-infection treatment and treatment significantly reduced levels of infection, virus output, DENV protein expression and genome copy number. These results suggest that these VDR agonists have the potential for future development as effective anti-DENV agents.
Topics: Calcitriol; Cells, Cultured; Dengue; Dengue Virus; Humans; Imidazoles; Immunosuppressive Agents; Receptors, Calcitriol; Virus Replication
PubMed: 32616772
DOI: 10.1038/s41598-020-67783-z -
British Journal of Pharmacology Aug 2017Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and...
BACKGROUND AND PURPOSE
Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish.
EXPERIMENTAL APPROACH
A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae. Selectivity was assessed by evaluation of non-ocular intersegmental vasculature development. Safety pharmacology examined visual behaviour and retinal histology in larvae. Molecular mechanisms of action were scrutinized using expression profiling of target mRNAs and miRNAs in larval eyes.
KEY RESULTS
Library screening identified 10 compounds which significantly inhibited HV developmental angiogenesis. The validated hit calcitriol selectively demonstrated dose-dependent attenuation of HV development. In agreement, vitamin D receptor (VDR) agonists paricalcitol, doxercalciferol, maxacalcitol, calcipotriol, seocalcitol, calcifediol and tacalcitol significantly and selectively attenuated HV development. VDR agonists induced minor ocular morphology abnormalities and affected normal visual function. Calcitriol induced a three to sevenfold increase in ocular dre-miR-21 expression. Consistently, all-trans-retinoic acid attenuated HV development and increased ocular dre-miR-21 expression. Interestingly, zebrafish ocular vegfaa and vegfab expression was significantly increased while, vegfc, flt1 and kdrl expression was unchanged by calcitriol.
CONCLUSION AND IMPLICATIONS
These studies identified VDR agonists as significant and selective anti-angiogenics in the developing vertebrate eye and miR21 as a key downstream regulated miRNA. These targets should be further evaluated as molecular hallmarks of, and therapeutic targets for pathological ocular neovascularization.
Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Calcitriol; Eye; Larva; MicroRNAs; Neovascularization, Physiologic; Receptors, Calcitriol; Tretinoin; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins
PubMed: 28547797
DOI: 10.1111/bph.13875 -
Nutrients May 2021We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast...
We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast cancer patients ( = 581) in four different datasets were divided into those expressing higher (above median) and lower levels of VDR in pretreatment ER+ tumors. Across all datasets, TAM-treated patients with higher pretreatment tumor VDR expression exhibited significantly longer recurrence-free survival. Ingenuity pathway analysis identified autophagy and unfolded protein response (UPR) as top differentially expressed pathways between high and low VDR-expressing ER+ cancers. Activation of VDR with vitamin D (VitD), either calcitriol or its synthetic analog EB1089, sensitized MCF-7-derived, antiestrogen-resistant LCC9 human breast cancer cells to TAM, and attenuated increased UPR and pro-survival autophagy. Silencing of VDR blocked these effects through the IRE1α-JNK pathway. Further, silencing of VDR impaired sensitivity to TAM in antiestrogen-responsive LCC1 cells, and prevented the effects of calcitriol and EB1089 on UPR and autophagy. In a preclinical mouse model, dietary VitD supplementation induced VDR activation and reduced carcinogen-induced ER+ mammary tumor incidence. In addition, IRE1α-JNK signaling was downregulated and survival autophagy was inhibited in mammary tumors of VitD-supplemented mice. Thus, activation of VDR is predictive of reduced risk of breast cancer recurrence in ER+ patients, possibly by inhibiting antiestrogen-promoted pro-survival autophagy.
Topics: Animals; Autophagy; Breast; Breast Neoplasms; Calcitriol; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoribonucleases; Estrogen Antagonists; Estrogen Receptor Modulators; Female; Humans; MCF-7 Cells; Mice; Protein Serine-Threonine Kinases; Receptors, Calcitriol; Tamoxifen; Vitamin D
PubMed: 34069442
DOI: 10.3390/nu13051715