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- Calcitriol and its analogues enhance the antiproliferative activity of gefitinib in breast cancer cells. [REVIEW]
- J Steroid Biochem Mol Biol 2014 Dec 12.
Coexpression of EGFR and HER2 has been associated with poor disease outcome, high rates of metastasis and resistance to conventional treatments in breast cancer. Gefitinib, a tyrosine kinase inhibitor, reduces both cell proliferation and tumor growth of breast cancer cells expressing EGFR and/or HER2. On the other hand, calcitriol and some of its synthetic analogs are important antineoplastic agents in different breast cancer subtypes. Herein, we evaluated the effects of the combined treatment of gefitinib with calcitriol or its analogs on cell proliferation in breast cancer cells. The presence of EGFR, HER2 and vitamin D receptor were evaluated by Western blot in two established breast cancer cell lines: SUM-229PE, SKBR3 and a primary breast cancer-derived cell line. The antiproliferative effects of gefitinib alone or in combination with calcitriol and its analogs, calcipotriol and EB1089, were assessed by growth assay using a DNA content-based method. Inhibitory concentrations on cell proliferation were calculated by non-linear regression analysis using sigmoidal fitting of dose-response curves. Pharmacological effects of the drug combinations were calculated by the Chou-Talalay method. Phosphorylation of ERK1/2 MAPK was evaluated by Western blot. Gene expression of EGFR, HER2 and BIM was assessed by real time PCR. BIM protein levels were analyzed in cells by flow cytometry. The effects of the drugs alone or combinated on cell cycle phases were determined using propidium iodide. Apoptosis was evaluated by detection of subG1 peak and determination of active caspase 3 by flow cytometry. Gefitinib, calcitriol, calcipotriol and EB1089 inhibited cell proliferation in a dose dependent manner by reducing percentages of cells in G2/M phase. The combinations of gefitinib with calcitriol or its analogs were more effective to inhibit cell growth than each compound alone in all breast cancer cells studied. The gene expression of EGFR and HER2 was downregulated and not affected, respectively, by the combined treatment. Furthermore, phosphorylation of ERK 1/2 was inhibited a greater extent in co-treated cells than in the cells treated with alone compounds. The combination of gefitinib with calcitriol or their synthetic analogs induced apoptosis in SUM-229PE cells, this was shown by the significant upregulation of BIM protein levels, higher percentages of cells in subG1 peak and increase of caspase 3-positive cells. The combination of gefitinib with calcitriol or their synthetic analogs resulted in a greater antiproliferative effect than with either of the agents alone in EGFR and HER2 positive breast cancer cells. The mechanistic explanation for these results includes downregulation of MAPK signaling pathway, decrease of cells in G2/M phase and induction of apoptosis mediated by upregulation of BIM and activation of caspase 3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
- Comparison effect of loading calcitriol and titrating calcitriol treatment to control hypocalcemia after parathyroidectomy in chronic kidney disease: randomized control trial, open labeled. [Journal Article]
- J Med Assoc Thai 2014 Nov.:S56-61.
Postoperative parathyroidectomy hypocalcemia probably results from acute reversal of the parathyroid hormone induced contribution of bone to maintain serum calcium concentration.Compare the effective treatment of calcitriol regimens (loaded and titrated) in control hypocalcemic hyperparathyroid (HPT) patients who were referred for parathyroidectomy.A randomized control, open labeled study of 25 patients who underwent parathyroidectomy in Rajavithi Hospital from August 2009 to September 2010 was conducted. The authors randomized 25 patients with chronic kidney disease in two treatment arms of calcitriol (A: Titrated dose regimen, B: Loaded dose regimen), that met criteria. Biochemical factors available within 2 weeks before and after surgery were recorded and analyzed.No significant difference was observed in amount of calcium gluconate intravenous use, hypocalcemia and hospital admission durations between titrated and loaded regimen groups, i.e., p = 0.160, 0.645 and 0.460, respectively. Loaded regimen ameliorated the mean reduction of day 7 postoperative mean change of serum calcium level by 0.33±0.99 mg/dl and median change by 2.88 mg/dl (min, max = -0.80, 5.64) compared with titrate regimen mean change ofserum calcium level by 2.68±2.16 mg/dl; median change 0.28 mg/dl (min, max = -0.84, 1.80) with significance, p = 0.036.Loaded calcitriol regimen was superior to titrated calcitriol regimen compared with the control group the first 7 days postparathyroidectomy. Amount of calcium gluconate intravenous used, hypocalcemia and duration of hospital stay did not show any significance.
- Erratum to: Calcitriol resistance in hemodialysis patients with secondary hyperparathyroidism. [JOURNAL ARTICLE]
- Int Urol Nephrol 2014 Dec 14.
- Decreased expression of CYP27B1 correlates with the increased aggressiveness of ovarian carcinomas. [JOURNAL ARTICLE]
- Oncol Rep 2014 Dec 11.
CYP27B1 hydroxylates 25-hydroxyvitamin D3 in position C1α into biologically active 1,25-dihydroxyvitamin D3, calcitriol. CYP27B1 is expressed in normal tissues and tumors. Since calcitriol indicates anticancer activities and CYP27B1 expression can be deregulated during malignant progression, we analyzed its expression in ovarian cancers in relation to pathomorphological features of tumors and overall survival (OS). Expression of CYP27B1 was evaluated in 61 ovarian tumors, 18 metastases and 10 normal ovaries. Normal ovarian epithelium showed the highest levels CYP27B1 with a significant decrease in its expression in ovarian cancers. Both poorly differentiated primary tumors and metastases showed the lowest level of CYP27B1 expression, while non-metastasizing tumors showed a higher CYP27B1 level than tumors that developed metastases. The expression of CYP27B1 was positively correlated with a lower proliferation rate, lower dynamism of tumor growth and tumor infiltrating lymphocyte response. Furthermore, CYP27B1 expression was negatively correlated with tumor cell modeling of their microenvironment. CYP27B1 expression was also associated with longer OS time. In summary, our results suggest that local expression of CYP27B1 in ovarian tumor cells can modify their behavior and promote a less aggressive phenotype by affecting local concentrations of active of vitamin D levels within the tumor microenvironment.
- Inhibitory effects of imatinib on vitamin D3 synthesis in human keratinocytes. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Dec 10.
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of the BCR‑ABL1 fusion gene, a constitutively active, oncogenic tyrosine kinase that is responsible for the clinical features of CML. Tyrosine kinase inhibitors, such as imatinib, have markedly altered the treatment of CML. However, tyrosine kinase inhibitors are associated with side effects on bone metabolism, in adult and pediatric patients. Vitamin D3 is involved in the complex cycle of bone remodeling, therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line, using commercially available enzyme assays. Imatinib was shown to significantly reduce the production of calcidiol and calcitriol. Based on interaction studies of imatinib with the cytochrome P450 (CYP450) inhibitors VID400 and ketoconazole, it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by CYP27B1, which is involved in vitamin D3 metabolism.
- Hypercalcemia induced by rosai-dorfman disease in a hemodialysis patient: histological evidence of extrarenal calcitriol overproduction. [Journal Article]
- Intern Med 2014; 53(24):2783-7.
Rosai-Dorfman disease (RDD) is a rare disorder characterized by the proliferation of histiocytes in the sinus of the affected lymph nodes, which leads to massive lymphadenopathy. RDD usually presents as an increased inflammatory response and lymph node swelling. We herein report the case of a hemodialysis patient with a fever, hypercalcemia and increased serum calcitriol level who was histologically diagnosed to have RDD. Immunohistochemistry revealed an increased expression of 1α-hydroxylase by histiocytes in the dilated sinus, indicating the extrarenal overproduction of calcitriol. Treatment with oral prednisolone decreased the serum levels of inflammatory markers and calcitriol, normalized the serum calcium level and mitigated the systemic lymph node enlargement.
- A cis-acting element in the promoter of human ether à go-go 1 potassium channel gene mediates repression by calcitriol in human cervical cancer cells. [JOURNAL ARTICLE]
- Biochem Cell Biol 2014 Oct 22.:1-8.
The human ether à go-go 1 potassium channel (hEAG1) is required for cell cycle progression and proliferation of cancer cells. Inhibitors of hEAG1 activity and expression represent potential therapeutic drugs in cancer. Previously, we have shown that hEAG1 expression is downregulated by calcitriol in a variety of cancer cells. Herein, we provided evidence on the regulatory mechanism involved in such repressive effect in cells derived from human cervical cancer. Our results indicate that repression by calcitriol occurs at the transcriptional level and involves a functional negative vitamin D response element (nVDRE) E-box type in the hEAG1 promoter. The described mechanism in this work implies that a protein complex formed by the vitamin D receptor-interacting repressor, the vitamin D receptor, the retinoid X receptor, and the Williams syndrome transcription factor interact with the nVDRE in the hEAG1 promoter in the absence of ligand. Interestingly, all of these transcription factors except the vitamin D receptor-interacting repressor are displaced from hEAG1 promoter in the presence of calcitriol. Our results provide novel mechanistic insights into calcitriol mode of action in repressing hEAG1 gene expression.
- Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism. [JOURNAL ARTICLE]
- Kidney Int 2014 Dec 10.
Calcitriol, a powerful regulator of phosphate metabolism and immune response, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney and macrophages. Renal 1α-hydroxylase expression is suppressed by Klotho and FGF23, the expression of which is stimulated by calcitriol. Interferon γ (INFγ) regulates 1α-hydroxylase expression in macrophages through transcription factor interferon regulatory factor-1. INFγ-signaling includes Janus kinase 3 (JAK3) but a role of JAK3 in the regulation of 1α-hydroxylase expression and mineral metabolism has not been shown. Thus, the impact of JAK3 deficiency on calcitriol formation and phosphate metabolism was measured. Renal interferon regulatory factor-1 and 1α-hydroxylase transcript levels, serum calcitriol and FGF23 levels, intestinal phosphate absorption as well as absolute and fractional renal phosphate excretion were significantly higher in jak3 knockout than in wild-type mice. Coexpression of JAK3 increased the phosphate-induced current in renal sodium-phosphate cotransporter-expressing Xenopus oocytes. Thus, JAK3 is a powerful regulator of 1α-hydroxylase expression and phosphate transport. Its deficiency leads to marked derangement of phosphate metabolism.Kidney International advance online publication, 10 December 2014; doi:10.1038/ki.2014.371.
- A rare cause of seizures, parkinsonian, and cerebellar signs: brain calcinosis secondary to thyroidectomy. [Journal Article]
- N Am J Med Sci 2014 Oct; 6(10):540-2.
Post-thyroidectomy hypoparathyroidism presenting with Parkinsonian features and seizures with extensive intracranial calcifications is uncommon. Acquired intracranial calcification that affects structures other than the basal ganglia is rare.We report a case of a 45-year-old woman with a history of total thyroidectomy who presented with Parkinsonian features, cerebellar signs, and seizures. Brain imaging revealed extensive intracranial calcifications secondary to long-standing hypoparathyroidism. The patient was treated with intravenous (IV) calcium gluconate therapy and shifted to oral calcium and calcitriol therapy. Her symptoms improved markedly. At four months of follow up, the patient had not suffered another episode of seizure and was being gradually weaned off anti-Parkinsonian therapy.This case describes the rare finding of extensive intracranial calcifications in a case of iatrogenic hypoparathyroidism secondary to thyroidectomy with its wide array of features and its remarkable response to restoration of calcium levels to normal limits.
- Modulators of Vitamin D Nuclear Receptor: Recent Sdvances from Structural Studies. [JOURNAL ARTICLE]
- Curr Top Med Chem 2014 Dec 7.
(1,25(OH)2D3, or calcitriol) regulate numerous biological functions. Therefore, VDR represents an important therapeutic target in the treatment of various diseases such as cancers, psoriasis, rickets, renal osteodystrophy, and autoimmune dysfunctions. Despite the number of newly synthesized 1,25(OH)2D3 analogues, the need for highly potential modulators of VDR with precise cell-, gene- or coregulator-selectivity still exists. The information coming from the analysis of crystal structures of VDR-ligand complexes remains one of the most powerful tools to explain and validate theproperties of the compounds and, furthermore, to gain new rationales for their modification. The number of reports on VDR-ligand recognition is constantly rising, and herein we review the recently published structural data. With the emphasis on the most promising compounds, such as secosteroidal compounds and 1,25(OH)2D3 mimics, we also highlight other natural ligands for VDR, evidence for the existence of an alternative ligand binding site within LBP, and identification of novel VDR modulators.