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Basile V, Allegra A, Marini HR, Berretta M, Granata B, Freni J, Puzzolo D, Stagno F, Midiri P, Urzì Brancati V, Minutoli L. Influence of Vitamin D and Its Analogues in Type-B Lymphomas. Curr Oncol 2025; 32:135. [PMID: 40136339 PMCID: PMC11941339 DOI: 10.3390/curroncol32030135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 03/27/2025] Open
Abstract
Lymphomas represent a heterogeneous group of blood tumors, generally divided into non-Hodgkin lymphoma (NHL) (90% of all lymphomas) and Hodgkin lymphoma (HL). High-grade NHL can rapidly progress so that new strategies and potentially therapeutical options are needed. Recently, it was shown that Vitamin D (VitD) inhibits the growth of cancer cells, controls their invasion and metastasis, and strengthens the antitumor activity of various types of chemotherapeutic anticancer agents. Therefore, we reviewed the recent literature about the influence of VitD and its analogues (VDAs) on the treatment and the prognosis of B-cell lymphomas. As to the in vitro studies in different cell lines, VitD3 and VDAs enhanced the anti-proliferative efficacy of various chemotherapeutics and increased the expression of VitD receptor. In in vivo studies, blood levels of VitD were considered: higher values of plasma bioavailable VitD were correlated with better progression-free survival (PFS) and overall survival (OS), while an unfavorable PFS and OS were observed in VitD deficient groups. No clinical trial was made on the analogs, thus confirming the absence of in vivo positive role of these synthetic drugs. In conclusion, higher levels of circulating VitD are related to improved OS, reduced cancer-specific mortality, and better disease-free survival. VitD and analogs showed also positive effects in in vitro studies, while only VitD was able to improve clinical parameters. Furthermore, a complex approach with plant-based diet, adequate levels for motor exercise, and/or eventual VitD supplementation could be a valuable strategy to challenge lymphomas.
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Affiliation(s)
- Valerio Basile
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy; (A.A.); (F.S.)
| | - Herbert Ryan Marini
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Barbara Granata
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - José Freni
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Domenico Puzzolo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Fabio Stagno
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy; (A.A.); (F.S.)
| | - Paola Midiri
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Valentina Urzì Brancati
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
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El-Alfy NZI, Emam AAK, Mahmoud MF, Morgan ONM, El-Ashry SRGE. Potential protection by vitamin D against DNA fragmentation and bone marrow cytotoxicity induced by chloramphenicol. Toxicol Rep 2024; 13:101828. [PMID: 39654996 PMCID: PMC11626822 DOI: 10.1016/j.toxrep.2024.101828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 12/12/2024] Open
Abstract
Vitamin D (Vit D) has gained significant attention in health research recently as a result of its potential protective effects against various cellular damages. This study aimed to investigate the ability of vitamin D to mitigate deoxyribonucleic acid (DNA) fragmentation in liver cells and bone marrow cytotoxicity induced by chloramphenicol (CAP). Sixty male albino mice were divided into six groups: control, chloramphenicol-treated (250 and 500 mg/kg body weight, 5 days per week for 4 weeks), vitamin D-treated (800 IU/kg body weight, 5 days per week for 4 weeks) and vitamin D plus chloramphenicol-treated groups. Results of DNA fragmentation test revealed that oral treatment with low and high doses of CAP significantly increased the frequency of DNA fragmentation in liver cells in comparison with the control, whereas oral treatment with vitamin D alone or plus low and high doses of chloramphenicol significantly reduced the genotoxicity in liver cells in comparison with the control group. Micronucleus analysis showed that CAP treatment at low and high doses significantly increased micronuclei formation and cytotoxicity in bone marrow cells. However, vitamin D significantly reduced the micronuclei formation in bone marrow cells of mice treated with chloramphenicol. Vitamin D alone showed no significant difference in the frequency of micronuclei and bone marrow cytotoxicity compared to the control group. Accordingly, further research exploring the mechanisms underlying the protective effects of vitamin D and investigating optimal dosing regimens is warranted. Also, clinical studies evaluating the efficacy of vitamin D supplementation to mitigate the adverse effects of chloramphenicol in human patients are recommended.
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Affiliation(s)
- Nagla Zaky Ibrahim El-Alfy
- Biological and Geological Sciences Department, Faculty of Education, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo 11341, Egypt
| | - Asmaa Ahmed Khaled Emam
- Biological and Geological Sciences Department, Faculty of Education, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo 11341, Egypt
| | - Mahmoud Fathy Mahmoud
- Biological and Geological Sciences Department, Faculty of Education, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo 11341, Egypt
| | - Omnia Nabeel Mohamed Morgan
- Biological and Geological Sciences Department, Faculty of Education, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo 11341, Egypt
| | - Sally Ramadan Gabr Eid El-Ashry
- Biological and Geological Sciences Department, Faculty of Education, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo 11341, Egypt
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Li JH, Hsin PY, Hsiao YC, Chen BJ, Zhuang ZY, Lee CW, Lee WJ, Vo TTT, Tseng CF, Tseng SF, Lee IT. A Narrative Review: Repurposing Metformin as a Potential Therapeutic Agent for Oral Cancer. Cancers (Basel) 2024; 16:3017. [PMID: 39272875 PMCID: PMC11394296 DOI: 10.3390/cancers16173017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/25/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Oral cancer, particularly oral squamous cell carcinoma (OSCC), is a significant global health challenge because of its high incidence and limited treatment options. Major risk factors, including tobacco use, alcohol consumption, and specific microbiota, contribute to the disease's prevalence. Recently, a compelling association between diabetes mellitus (DM) and oral cancer has been identified, with metformin, a widely used antidiabetic drug, emerging as a potential therapeutic agent across various cancers, including OSCC. This review explores both preclinical and clinical studies to understand the mechanisms by which metformin may exert its anticancer effects, such as inhibiting cancer cell proliferation, inducing apoptosis, and enhancing the efficacy of existing treatments. Preclinical studies demonstrate that metformin modulates crucial metabolic pathways, reduces inflammation, and impacts cellular proliferation, thereby potentially lowering cancer risk and improving patient outcomes. Additionally, metformin's ability to reverse epithelial-to-mesenchymal transition (EMT), regulate the LIN28/let-7 axis, and its therapeutic role in head and neck squamous cell carcinoma (HNSCC) are examined through experimental models. In clinical contexts, metformin shows promise in enhancing therapeutic outcomes and reducing recurrence rates, although challenges such as drug interactions, complex dosing regimens, and risks such as vitamin B12 deficiency remain. Future research should focus on optimizing metformin's application, investigating its synergistic effects with other therapies, and conducting rigorous clinical trials to validate its efficacy in OSCC treatment. This dual exploration underscores metformin's potential to play a transformative role in both diabetes management and cancer care, potentially revolutionizing oral cancer treatment strategies.
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Affiliation(s)
- Jui-Hsiang Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 33004, Taiwan
| | - Pei-Yi Hsin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yung-Chia Hsiao
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Bo-Jun Chen
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Zhi-Yun Zhuang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chiang-Wen Lee
- Department of Nursing, Division of Basic Medical Sciences, Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan
- Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi 61363, Taiwan
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Wei-Ju Lee
- School of Food Safety, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Thi Thuy Tien Vo
- Faculty of Dentistry, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam
| | - Chien-Fu Tseng
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei 10048, Taiwan
- Department of Dentistry, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 33004, Taiwan
| | - Shih-Fen Tseng
- Department of Emergency Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 33004, Taiwan
| | - I-Ta Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Cuomo RE. Serum 25-Hydroxyvitamin D and Five-Year Survival in Primary Colon Cancer: A Retrospective Cohort Study. Nutr Cancer 2024; 76:1008-1017. [PMID: 39126134 DOI: 10.1080/01635581.2024.2389580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
This study examined the link between serum 25-hydroxyvitamin D (25(OH)D) and mortality in patients with colon cancer. Using a clinical database from the University of California, serum 25(OH)D measures were averaged for the time following diagnosis until either the time of death or 5 years had elapsed. Analytical methods included the use of Generalized Additive Models (GAM), logistic regression, and Cox proportional hazards models to examine non-linear relationships and the impact of 25(OH)D on 5-year mortality. This study assessed 1,602 patients with colon cancer having a median 25(OH)D of 31.8 ng/mL and a 5-year mortality rate of 22.7%. A significant association between higher post-diagnosis vitamin D levels and decreased 5-year mortality was observed. This association persisted after adjusting for disease severity and significant demographic confounders, in both a logistic regression model for 5-year mortality (OR = 0.79, 95% CI: 0.66-0.92, p < 0.001) and a cox proportional hazards model for survival (HR = 0.94, CI: 0.88-0.99, p = 0.048). GAM illustrated a steep increase in survival probability up to a plateau, suggesting a threshold effect beyond roughly 50.0 ng/mL. This study found a potential protective role of vitamin D in the survival of colon cancer patients, supporting the correction of levels below 25 ng/mL but ideally above 50 ng/mL.
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Affiliation(s)
- Raphael E Cuomo
- School of Medicine, University of California, San Diego, CA, USA
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Bartoszewska E, Molik K, Woźniak M, Choromańska A. Telomerase Inhibition in the Treatment of Leukemia: A Comprehensive Review. Antioxidants (Basel) 2024; 13:427. [PMID: 38671875 PMCID: PMC11047729 DOI: 10.3390/antiox13040427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/26/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Leukemia, characterized by the uncontrolled proliferation and differentiation blockage of myeloid or lymphoid precursor cells, presents significant therapeutic challenges despite current treatment modalities like chemotherapy and stem cell transplantation. Pursuing novel therapeutic strategies that selectively target leukemic cells is critical for improving patient outcomes. Natural products offer a promising avenue for developing effective chemotherapy and preventive measures against leukemia, providing a rich source of biologically active compounds. Telomerase, a key enzyme involved in chromosome stabilization and mainly active in cancer cells, presents an attractive target for intervention. In this review article, we focus on the anti-leukemic potential of natural substances, emphasizing vitamins (such as A, D, and E) and polyphenols (including curcumin and indole-3-carbinol), which, in combination with telomerase inhibition, demonstrate reduced cytotoxicity compared to conventional chemotherapies. We discuss the role of human telomerase reverse transcriptase (hTERT), particularly its mRNA expression, as a potential therapeutic target, highlighting the promise of natural compounds in leukemia treatment and prevention.
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Affiliation(s)
- Elżbieta Bartoszewska
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (K.M.)
| | - Klaudia Molik
- Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; (E.B.); (K.M.)
| | - Marta Woźniak
- Department of Clinical and Experimental Pathology, Division of General and Experimental Pathology, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland;
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Djulejic V, Petrovic B, Jevtic J, Vujacic M, Clarke BL, Cirovic A, Cirovic A. The role of cadmium in the pathogenesis of myeloid leukemia in individuals with anemia, deficiencies in vitamin D, zinc, and low calcium dietary intake. J Trace Elem Med Biol 2023; 79:127263. [PMID: 37499549 DOI: 10.1016/j.jtemb.2023.127263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/27/2023] [Accepted: 07/10/2023] [Indexed: 07/29/2023]
Abstract
Iron deficiency, vitamin D deficiency and low calcium diet are frequent health problems with severe long- term consequences. Upon absorption from the duodenum, cadmium binds to transferrin, and cells with the highest density of transferrin receptor 1 (TfR1) take up the majority of the circulating cadmium. Nowadays, it is clear that individuals with iron deficiency anemia have increased blood levels of cadmium because of higher absorption rate, mediated by divalent metal transporter 1 (DMT1). However, the transient receptor potential vanilloid receptor 6 (TRPV6), known as a calcium carrier, is able to bind and transport cadmium as well. In the case of low calcium diet or vitamin D deficiency, TRPV6 may be overexpressed in the intestine and kidney tubules and absorbs (re-uptake in the case of renal tubules) cadmium in larger quantities, resulting in an increased cadmium blood levels. We speculate that the final event in the case of low calcium dietary diet and/or vitamin D deficiency is similar to what is observed in the case of iron deficiency, that cells with the highest levels of TfR1 (for example, megakaryocyte/erythrocyte progenitors and pro-erythroblasts) take up most of the circulating cadmium, which is powerful malignancy inductor, leading to appearance of acute myeloid leukemia (AML).
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Affiliation(s)
- Vuk Djulejic
- University of Belgrade, Faculty of Medicine, Institute of Anatomy, Belgrade, Serbia
| | - Bojan Petrovic
- Institute for Orthopedic Surgery "Banjica", Mihaila Avramovića 28, Belgrade, Serbia
| | - Jovan Jevtic
- University of Belgrade, Faculty of Medicine, Institute of Pathology, Belgrade, Serbia
| | - Marko Vujacic
- Institute for Orthopedic Surgery "Banjica", Mihaila Avramovića 28, Belgrade, Serbia
| | - Bart L Clarke
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
| | - Ana Cirovic
- University of Belgrade, Faculty of Medicine, Institute of Anatomy, Belgrade, Serbia
| | - Aleksandar Cirovic
- University of Belgrade, Faculty of Medicine, Institute of Anatomy, Belgrade, Serbia.
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Törzsök P, Van Goubergen J, Pichler M, Pichler R, Santer FR. Isochromosome 12p Formation Regulates Vitamin D Metabolism in Testicular Cancer. Nutrients 2023; 15:nu15102384. [PMID: 37242266 DOI: 10.3390/nu15102384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Isochromosome 12p (iChr12p) is typical in almost all invasive testicular cancers. Increased copy number of genes on 12p is associated with the development of a clinically manifest tumor; however, the causative genes have not yet been identified. Chromosome 12 harbors many genes involved in Vitamin D metabolism. RNAseq analysis of Vitamin D receptor (VDR) genes from the TCGA cohort revealed that clustering of VDR expression signatures could differentiate between pure seminomas and non-seminomatous germ cell tumors (NSGCT). Using TCGA mRNA expression of anabolic (CYP2R1, CYP27A1 and CYP27B1) and catabolic (CYP24A1) Vitamin D enzymes, positive (PTHLH, IFNG, and TNF) and negative (FGF23) feedback regulators could also clearly distinguish between pure seminomas and NSGCT. We hypothesize that the regulation of Vitamin D metabolism might be disturbed through iChr12p formation, influencing testicular carcinogenesis via increased FGF23 and PTHLH expression. While FGF23 represses CYP27B1 and activates catabolism of active hormone, increased PTHLH secretion can lead to hypercalcemia via inactivation of VDR. In conclusion, testicular cancer is associated with extensive modifications in intratesticular Vitamin D homeostasis. Further research is needed to clarify whether Vitamin D deficiency causes the formation of iChr12p and whether Vitamin D deficiency via iChr12p genomic aberration is involved in testicular carcinogenesis.
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Affiliation(s)
- Peter Törzsök
- Department of Urology and Andrology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Jasper Van Goubergen
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
- Translational Oncology, University Hospital of Augsburg, 86156 Augsburg, Germany
| | - Renate Pichler
- Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Frédéric R Santer
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Asoubar S, Esfahani A, Vahedi A, Mohammadi SM, Zarezadeh M, Hamedi-Kalajahi F, Ghoreishi Z, Roshanravan N. Responsible enzymes for metabolizing vitamin D in patients with acute leukemia and the relationship with treatment outcomes: a case-control study. Leuk Lymphoma 2022; 63:1949-1955. [DOI: 10.1080/10428194.2022.2056174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Sadegh Asoubar
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Esfahani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Vahedi
- Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyede-Momeneh Mohammadi
- Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Meysam Zarezadeh
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Hamedi-Kalajahi
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Ghoreishi
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Barbier C, Mansour A, Ismailova A, Sarmadi F, Scarlata DA, Bouttier M, Zeitouni C, Wang C, Gleason JL, White JH. Molecular mechanisms of bifunctional vitamin D receptor agonist-histone deacetylase inhibitor hybrid molecules in triple-negative breast cancer. Sci Rep 2022; 12:6745. [PMID: 35468986 PMCID: PMC9038752 DOI: 10.1038/s41598-022-10740-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/29/2022] [Indexed: 11/24/2022] Open
Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), and its analogues signal through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor, and have been extensively investigated as anticancer agents. 1,25D and its analogs have potential in combination therapies because they exhibit synergistic activities with other anticancer agents such as histone deacetylase inhibitors (HDACi). We have developed a series of hybrid molecules that combine HDACi within the backbone of a VDR agonist and thus represent fully integrated bifunctional molecules. They exhibit anti-tumor efficacy in reducing tumor growth and metastases in an aggressive model of triple-negative breast cancer. However, their solubility is limited by their hydrophobic diarylpentane cores. Our goals here were two-fold: (1) to improve the solubility of hybrids by introducing nitrogen into diarylpentane cores, and (2) to investigate the molecular mechanisms underlying their anti-tumor efficacy by performing comparative gene expression profiling studies with 1,25D and the potent HDACi suberoylanilide hydroxamic acid (SAHA). We found that substituting aryl with pyrydyl rings did not sacrifice bifunctionality and modestly improved solubility. Notably, one compound, AM-193, displayed enhanced potency as a VDR agonist and in cellular assays of cytotoxicity. RNAseq studies in triple negative breast cancer cells revealed that gene expression profiles of hybrids were very similar to that of 1,25D, as was that observed with 1,25D and SAHA combined. The effects of SAHA alone on gene expression were limited and distinct from those 1,25D or hybrids. The combined results suggest that efficacy of hybrids arises from targeting HDACs that do not have a direct role in gene regulation. Moreover, pathways analysis revealed that hybrids regulate numerous genes controlling immune cell infiltration into tumors and suppress the expression of several secreted molecules that promote breast cancer growth and metastasis.
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Affiliation(s)
- Camille Barbier
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Ali Mansour
- Departments of Chemistry, McGill University, Montreal, QC, Canada
| | - Aiten Ismailova
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Fatemeh Sarmadi
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - David A Scarlata
- Departments of Chemistry, McGill University, Montreal, QC, Canada
| | | | - Camille Zeitouni
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Catherine Wang
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - James L Gleason
- Departments of Chemistry, McGill University, Montreal, QC, Canada.
| | - John H White
- Departments of Physiology, McGill University, Montreal, QC, Canada.
- Departments of Medicine, McGill University, Montreal, QC, Canada.
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Hazem RM, Antar SA, Nafea YK, Al-Karmalawy AA, Saleh MA, El-Azab MF. Pirfenidone and vitamin D mitigate renal fibrosis induced by doxorubicin in mice with Ehrlich solid tumor. Life Sci 2022; 288:120185. [PMID: 34861286 DOI: 10.1016/j.lfs.2021.120185] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 02/05/2023]
Abstract
AIMS Doxorubicin is a prominent anticancer agent. However, its organotoxic potential has restricted its clinical use. The current study was performed to investigate the protective effect of pirfenidone and vitamin D against doxorubicin-triggered nephrotoxicity. MATERIALS AND METHODS Female albino mice (5 mice per group) were inoculated with Ehrlish scites carcinoma (EAC) cells for induction of solid tumor and treated with pirfenidone 500 mg/kg orally (p.o.) or vitamin D 0.5 μg/kg intraperitonially (i.p.), either individually or combined with single doxorubicin (15 mg/kg; i.p.) dose. Additionally, 5 mice were served as a normal group. Treatment commenced 7 days after inoculation of Ehrlich ascites carcinoma cells and lasted for 14 days. KEY FINDINGS Pirfenidone and vitamin D enhanced the anti-tumor activity of doxorubicin, by decreasing tumor weight and volume. Doxorubicin increased kidney weights, creatinine, urea levels and collagen fibers deposition within renal tubules. Moreover, doxorubicin was associated with overexpression of nuclear factor-kappa B (NF-κB) and alpha-smooth muscle actin (α-SMA) as both parameters assessed by kidney immunohistochemistry. Furthermore, histological signs of large areas of interistital fibrosis and cellular infiltration were significant with sole doxorubicin treatment. Notably, doxorubicin elevated both MCP1 and TGFB1 gene expression in addition to increasing the protein expression of Smad3 and Jun N-terminal Kinase-1 (JNK1) while decreasing that of Smad7. Pirfenidone in combined with vitamin D abolished doxorubicin-evoked disturbances in the aforementioned parameters and blunted all histological alterations. SIGNIFICANCE Pirfenidone and vitamin D demonstrated a viable approach to suppress the nephrotoxicity initiated by doxorubicin through inhibiting the JNK1 and MCP-1 pathways.
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Affiliation(s)
- Reem M Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Samar A Antar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
| | - Yossef K Nafea
- Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Canada
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
| | - Mohamed A Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, the United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Mona F El-Azab
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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Vitamin D Analogs Regulate the Vitamin D System and Cell Viability in Ovarian Cancer Cells. Int J Mol Sci 2021; 23:ijms23010172. [PMID: 35008598 PMCID: PMC8745402 DOI: 10.3390/ijms23010172] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may cause hypercalcemia. We hypothesized that newly developed, low calcemic, vitamin D analogs (an1,25Ds) may be used as anticancer agents instead of calcitriol in ovarian cancer cells. METHODS We used two patient-derived high-grade serous ovarian cancer (HGSOC) cell lines with low (13781) and high (14433) mRNA expression levels of the gene encoding 1,25-dihydroxyvitamin D3 24-hydroxylase CYP24A1, one of the main target genes of calcitriol. We tested the effect of calcitriol and four structurally related series of an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202) on cell number, viability, the expression of CYP24A1, and the vitamin D receptor (VDR). RESULTS CYP24A1 mRNA expression increased in a concentration-dependent manner after treatment with all compounds. In both cell lines, after 4 h, PRI-5202 was the most potent analog (in 13781 cells: EC50 = 2.98 ± 1.10 nmol/L, in 14433 cells: EC50 = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC50 = n/d, in 14433 cells: EC50 = n/d). This difference among the analogs disappeared after 5 days of treatment. The 13781 cells were more sensitive to the an1,25Ds compared with 14433 cells. The an1,25Ds increased nuclear VDR levels and reduced cell viability, but only in the 13781 cell line. CONCLUSIONS The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing CYP24A1 expression was cell line- and chemical structure-dependent. Therefore, choosing sensitive cancer cell lines and further optimization of the analogs' structure might lead to new treatment options against ovarian cancer.
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Bach A, Fleischer H, Wijayawardena B, Thurow K. Optimization of Automated Sample Preparation for Vitamin D Determination on a Biomek i7 Workstation. SLAS Technol 2021; 26:615-629. [PMID: 34282678 DOI: 10.1177/24726303211030291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Vitamin D belongs to the fat-soluble vitamins and is an integral part of bone metabolism. In the human body, a decreased vitamin D level can be an additional risk factor for diseases like cancer, diabetes, and mental diseases. As a result, an enormous increase in the demand for vitamin D testing has been observed in recent years, increasing the demand for powerful methods for vitamin D determination at the same time.Automation is the key factor in increasing sample throughput. This study compares three fully automated sample preparation methods for the determination of 25(OH)D2 and 25(OH)D3 in plasma and serum samples. Starting from a semiautomated reference method, the method is tested manually and subsequently fully automated on the Biomek i7 Workstation by integrating a centrifuge and a positive pressure extractor into the workstation. Alternatively, the centrifugation for the separation of protein aggregates and supernatant is replaced by a filter plate. Finally, the sample throughput is further increased by using phospholipid removal cartridges. The results show that phospholipid removal significantly increases the recovery rates in liquid chromatography-mass spectrometry. With the phospholipid removal cartridges, recovery rates of 97.36% for 25(OH)D2 and 102.5% for 25(OH)D3 were achieved, whereas with the automated classic automated preparation method, the recovery rates were 83.31% for 25(OH)D2 and 86.54% for 25(OH)D3. In addition to the technical evaluation, the different methods were also examined with regard to their economic efficiency. Finally, the qualitative and quantitative performance of the developed methods is benchmarked with a selected semiautomatic reference method.
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Affiliation(s)
- Anna Bach
- Center for Life Science Automation, University of Rostock, Rostock, Germany
| | - Heidi Fleischer
- Institute of Automation, University of Rostock, Rostock, Germany
| | | | - Kerstin Thurow
- Center for Life Science Automation, University of Rostock, Rostock, Germany
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Pirfenidone and Vitamin D Ameliorate Cardiac Fibrosis Induced by Doxorubicin in Ehrlich Ascites Carcinoma Bearing Mice: Modulation of Monocyte Chemoattractant Protein-1 and Jun N-terminal Kinase-1 Pathways. Pharmaceuticals (Basel) 2020; 13:ph13110348. [PMID: 33126642 PMCID: PMC7693623 DOI: 10.3390/ph13110348] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Treatment of breast cancer with doxorubicin causes numerous side effects, of which cardiac fibrosis is considered the main one. This study was designed to investigate the underlying molecular mechanisms for the potential anti-fibrotic effect of pirfenidone and vitamin D against doxorubicin-induced cardiac fibrosis. Seventy mice carrying solid Ehrlich’s ascites carcinoma (EAC) discs on the ventral side were treated with orally administered pirfenidone (500 mg/kg) and intraperitoneal injection of vitamin D (0.5 µg/kg) either individually or in combination with a doxorubicin (15 mg/kg; i.p.) single dose. All treatments commenced one week post-tumor inoculation and continued for 14 days. Compared to control EAC mice, the doxorubicin group showed a significant increase in heart and left ventricle weights, troponin T, and creatinine kinase serum levels. Furthermore, the doxorubicin group depicts a high expression of monocyte chemoattractant protein (MCP-1), nuclear factor-kappa B (NF-κB), transforming growth factor-beta 1 (TGF-β1), smad3, Jun N-terminal Kinase-1 (JNK1), and alpha-smooth muscle actin (α-SMA). Treatment with pirfenidone or vitamin D significantly decreased all of these parameters. Furthermore, the expression of smad7 was downregulated by doxorubicin and improved by pirfenidone or vitamin D. Furthermore, all treated groups showed a marked decrease in tumor weight and volume. Current data demonstrate that pirfenidone and vitamin D represent an attractive approach to ameliorate the cardiac fibrosis produced by doxorubicin through inhibiting both JNK1 signaling and MCP-1 inflammatory pathways, thus preserving heart function. Further, this combination demonstrated an anti-tumor effect to combat breast cancer.
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Farghali M, Ruga S, Morsanuto V, Uberti F. Can Brain Health Be Supported by Vitamin D-Based Supplements? A Critical Review. Brain Sci 2020; 10:brainsci10090660. [PMID: 32972010 PMCID: PMC7563709 DOI: 10.3390/brainsci10090660] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023] Open
Abstract
This review presents recent knowledge on the neuroprotective effects of vitamin D and their usefulness as oral supplementation when combined with other molecules, such as curcumin. A critical look at the effectiveness of vitamin D in this field is also provided. Vitamin D plays a crucial role in neuroprotection and in the cognitive decline associated with aging, where vitamin D’s levels are related to the levels of several neurotrophic factors. An important role of vitamin D has also been observed in the mechanism of neuroinflammation, which is the basis of several aging conditions, including cognitive decline and neurodegeration; furthermore, the neuroprotective effect of vitamin D in the cognitive decline of aging has recently been reported. For this reason, many food supplements created for humans contain vitamin D alone or combined with other molecules with antioxidant properties. However, recent studies also explored negative consequences of the use at a high dosage of vitamin D. Vitamin D in tissues or brain cells can also modulate calbindin-D28K, parvalbumin, and calretinin, and is involved in immune function, thanks also to the combination with curcumin. Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. In particular, curcumin is a potent immune-regulatory agent and its administration has been reported to attenuate cognitive impairments. These effects could be exploited in the future to control the mechanisms that lead to the brain decay typical of neurodegenerative diseases.
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15
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Grioli SM, Alonso EN, Mascaró E, Stabile SA, Ferronato MJ, Quevedo MA, Radivoy G, Facchinetti MM, Vitale CA, Curino AC. Structure-Activity Relationship Study of an Alkynylphosphonate and Vynilphosphonate Analogues of Calcitriol. Med Chem 2020; 17:230-246. [PMID: 32819231 DOI: 10.2174/1573406416999200818145115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 07/05/2020] [Accepted: 07/20/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND 1α,25-dihydroxy vitamin D3 (calcitriol) shows potent growth-inhibitory properties on different cancer cell lines, but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important to develop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG. OBJECTIVE The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyze by in silico studies, the chemical structure-biological function relationship of these molecules. METHODS We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modeling. RESULTS The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor activity was blunted, as no antiproliferative or anti-migratory effects were observed. By in silico assays, we demonstrated that SG analogue has a lower affinity for the VDRligand- binding domain than the EM1 compound due to lack of interaction with the important residues His305 and His397. CONCLUSION These results demonstrate that the chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.
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Affiliation(s)
- Silvina M Grioli
- Laboratorio de Quimica Organica, Instituto de Quimica del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Quimica (UNS), Bahia Blanca, 8000, Argentina
| | - Eliana N Alonso
- Laboratorio de Biología del Cancer, Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Departamento de Biologia, Bioquimica y Farmacia (UNS), Bahia Blanca, 8000, Argentina
| | - Evangelina Mascaró
- Laboratorio de Quimica Organica, Instituto de Quimica del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Quimica (UNS), Bahia Blanca, 8000, Argentina
| | - Santiago A Stabile
- Laboratorio de Quimica Organica, Instituto de Quimica del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Quimica (UNS), Bahia Blanca, 8000, Argentina
| | - María J Ferronato
- Laboratorio de Biología del Cancer, Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Departamento de Biologia, Bioquimica y Farmacia (UNS), Bahia Blanca, 8000, Argentina
| | - Mario A Quevedo
- Unidad de Investigacion y Desarrollo en Tecnologia Farmaceutica (UNITEFA-CONICET), Facultad de Ciencias Quimicas, Ciudad Universitaria, Universidad Nacional de Cordoba, Cordoba, 5000, Argentina
| | - Gabriel Radivoy
- Laboratorio de Quimica Organica, Instituto de Quimica del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Quimica (UNS), Bahia Blanca, 8000, Argentina
| | - María M Facchinetti
- Laboratorio de Biología del Cancer, Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Departamento de Biologia, Bioquimica y Farmacia (UNS), Bahia Blanca, 8000, Argentina
| | - Cristian A Vitale
- Laboratorio de Quimica Organica, Instituto de Quimica del Sur (INQUISUR), Universidad Nacional del Sur (UNS), CONICET, Departamento de Quimica (UNS), Bahia Blanca, 8000, Argentina
| | - Alejandro C Curino
- Laboratorio de Biología del Cancer, Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB), Universidad Nacional del Sur (UNS)-CONICET, Departamento de Biologia, Bioquimica y Farmacia (UNS), Bahia Blanca, 8000, Argentina
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Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications. Molecules 2020; 25:molecules25143219. [PMID: 32679655 PMCID: PMC7397283 DOI: 10.3390/molecules25143219] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 03/28/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agents.
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Effects of an Omega-3 and Vitamin D Supplement on Fatty Acids and Vitamin D Serum Levels in Double-Blinded, Randomized, Controlled Trials in Healthy and Crohn's Disease Populations. Nutrients 2020; 12:nu12041139. [PMID: 32325778 PMCID: PMC7230517 DOI: 10.3390/nu12041139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Two trials separately measured the bioavailability and impact on inflammation of a supplement taken daily containing 510 mg Docosahexaenoic acid (DHA), 344 mg Eicosapentaenoic acid (EPA), and 1000 IU of vitamin D (25-hydroxyvitamin D; 25(OH)D), for healthy and Crohn’s disease (CD) populations. Both trials were double blinded, randomized, placebo-controlled with cross-over. Participants were randomly allocated to groups A (placebo then supplement) or B (supplement then placebo). Both included a washout. Fatty acid (N-3 PUFAs) and vitamin D serum levels, plasma C-reactive protein (CRP), and stool calprotectin were measured before and after each treatment period. Outcome measures were analyzed using generalized linear mixed models, including terms for treatment, period, and a treatment-by-period interaction. The supplement significantly increased serum levels in healthy and CD groups for EPA (p < 0.001 and p < 0.001, respectively), Docosapentaenoic acid (p < 0.001 and 0.005), DHA (p < 0.001 and 0.006), the omega-3 index (p < 0.001 and 0.001), and (vitamin D (p < 0.001 and 0.027). CRP and calprotectin measures showed no evidence of a treatment effect on inflammation; however, model estimation was imprecise for both outcomes, hence further research is required to elucidate potential inflammation effects. The nutrient supplement increased serum levels of key N-3 PUFAs and vitamin D in both populations, showing the preparation was readily bioavailable.
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Zhang T, He L, Wang Z, Dong W, Sun W, Qin Y, Zhang P, Zhang H. Calcitriol enhances Doxorubicin-induced apoptosis in papillary thyroid carcinoma cells via regulating VDR/PTPN2/p-STAT3 pathway. J Cell Mol Med 2020; 24:5629-5639. [PMID: 32285621 PMCID: PMC7214146 DOI: 10.1111/jcmm.15224] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 02/28/2020] [Accepted: 03/13/2020] [Indexed: 12/29/2022] Open
Abstract
There is increasing evidence that vitamin D deficiency is the risk factor for multiple diseases, such as immune disorder, cardiovascular disease and cancer. Calcitriol is the active form of vitamin D with beneficial effects on anti‐cancer by binding vitamin D receptor (VDR). The primary aim of this study was to investigate the role of Calcitriol on papillary thyroid carcinoma (PTC) and explore the possible mechanism. We found nuclear VDR expression in PTC samples was negatively correlated with STAT3 hyperphosphorylation that indicated worse PTC clinicopathologic characteristics. Calcitriol treatment up‐regulated VDR and protein tyrosine phosphatase N 2 (PTPN2) expression, down‐regulated signal transducers and activators of transcription (STAT3) phosphorylation and thereby facilitating chemotherapy drug Doxorubicin‐induced apoptosis in PTC cell lines. However, the apoptosis‐promoting effect of Calcitriol and Doxorubicin co‐treatment was abrogated by STAT3 hyperphosphorylation, indicating suppression of STAT3 phosphorylation was essential for combined treatment of Calcitriol and Doxorubicin in PTC. Together, these results suggested that Calcitriol reinforced the sensitivity of PTC cells to Doxorubicin by regulating VDR/PTPN2/p‐STAT3 signalling pathway.
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Affiliation(s)
- Ting Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Liang He
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Zhihong Wang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Wei Sun
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Qin
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
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Torkko K, Till C, Tangen CM, Goodman PJ, Song X, Schenk JM, Lucia MS, Peters U, van Bokhoven A, Thompson IM, Neuhouser ML. Vitamin D Pathway and Other Related Polymorphisms and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial. Cancer Prev Res (Phila) 2020; 13:521-530. [PMID: 32102946 DOI: 10.1158/1940-6207.capr-19-0413] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/02/2020] [Accepted: 02/20/2020] [Indexed: 12/31/2022]
Abstract
Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case-control study in the Prostate Cancer Prevention Trial (PCPT). Cases (n = 1,128) and controls (n = 1,205) were frequency matched on age, first-degree relative with prostate cancer, and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy confirmed. We selected 21 SNPs in vitamin D-related genes (VDR, GC, C10orf88, CYP2R1, CYP24A1, CYP27B1, DHCR7, and NADSYN1) to test genotype and genotype-treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D-genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, body mass index, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and GC/rs222016 (finasteride OR = 1.37, placebo OR = 0.85; P interaction < 0.05), GC/rs222014 (finasteride OR = 1.36, placebo OR = 0.85; P interaction < 0.05), and CYP27B1/rs703842 (finasteride OR = 0.76, placebo OR = 1.10; P interaction < 0.05) among Caucasians, and C10orf88/rs6599638 (finasteride OR = 4.68, placebo OR = 1.39; P interaction < 0.05) among African-Americans. VDR/rs1544410 and CYP27B1/rs703842 had significant treatment interactions for high-grade disease among Caucasians (finasteride OR = 0.81, placebo OR = 1.40; P interaction < 0.05 and finasteride OR = 0.70, placebo OR = 1.28; P interaction < 0.05, respectively). Vitamin D-related SNPs influenced serum 25(OH)D, but gene-serum 25(OH)D effect modification for prostate cancer was marginally observed only for CYP24A1/rs2248359. In conclusion, evidence that vitamin D-related genes or gene-serum 25(OH)D associations influence prostate cancer risk is modest. We found some evidence for gene-finasteride interaction effects for prostate cancer in Caucasians and African-Americans. Results suggest only minimal associations of vitamin D with total or high-grade prostate cancer.
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Affiliation(s)
- Kathleen Torkko
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Cathee Till
- Division of Public Health Sciences, SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Catherine M Tangen
- Division of Public Health Sciences, SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Phyllis J Goodman
- Division of Public Health Sciences, SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Xiaoling Song
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jeannette M Schenk
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - M Scott Lucia
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Ulrike Peters
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Adrie van Bokhoven
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Ian M Thompson
- Christus Santa Rosa Hospital-Medical Center, San Antonio, Texas
| | - Marian L Neuhouser
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Raoufinejad K, Shamshiri AR, Pezeshki S, Chahardouli B, Hadjibabaie M, Jahangard-Rafsanjani Z, Gholami K, Rajabi M, Vaezi M. Oral calcitriol in hematopoietic recovery and survival after autologous stem cell transplantation: a randomized clinical trial. Daru 2019; 27:709-720. [PMID: 31713184 PMCID: PMC6895337 DOI: 10.1007/s40199-019-00306-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Calcitriol, the active metabolite of vitamin D, is an essential regulator in the hematopoiesis and immunity. However, knowledge revealing its influence on the immune and hematologic reconstitution after hematopoietic stem cell transplantation (HSCT) in clinical trials is very limited. OBJECTIVES The effects of calcitriol on short-term and long-term hematopoietic recovery, relapse-free survival (RFS) and overall survival (OS) in multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma following autologous peripheral blood HSCT were assessed. METHODS Eighty patients (age: 18-68 years) in complete remission were allocated 1:1 to two groups by balanced block randomization. Calcitriol 0.25 μg or placebo capsule was administered three times daily from transplantation to day 30. Absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet count (PC) were determined daily from transplantation to day 30. White blood cell count (WBC), PC, and hemoglobin concentration (HC) of days 180 and 365 were extracted from clinic files. A thorough examination for oral mucositis (OM) was completed daily during hospital stay. Adverse drug reactions (ADRs) as well as two-year RFS and OS were evaluated. RESULTS Median time to ANC engraftment (≥0.5 × 103/μl: 10.0 vs. 11.0 days; P = 0.98) and PC engraftment (≥20.0 × 103/μl: both 14.0 days; P = 0.58) was similar between groups. However, the median time to ALC recovery was significantly shorter in the calcitriol group (≥0.5 × 103/μl: 13.0 vs. 20.0 days; P < 0.001). Moreover, ALC recovery rates on day 15 (≥0.5 × 103/μl: 82.1% vs. 42.5%; P < 0.001) and on day 30 (≥1.0 × 103/μl: 91.7% vs. 57.5%; P = 0.001) was significantly higher with calcitriol. WBC, PC, and HC on days 180 and 365 were not significantly different between groups. None of the OM indices were modulated by calcitriol. All the ADRs were non-serious and mild, possibly or unlikely related to the intervention. In a median of 29 months follow-up, RFS was significantly better in the calcitriol group (77.0%, SE = 7.0% vs. 59.0%, SE = 8.0%; P = 0.03), albeit the OS was not affected (87.0%, SE = 5.0% vs. 92.0%, SE = 4.0%; P = 0.72). CONCLUSION Calcitriol could improve ALC recovery and RFS as a safe option post-HSCT. Graphical abstract Oral calcitriol 0.25 µg three times daily from transplantation to day 30 improved lymphocytes recovery and two-year relapse-free survival as a safe option in 80 patients of autologous hematopoietic stem cell transplantation in comparison with placebo.
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Affiliation(s)
- Kosar Raoufinejad
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, PO Box 14155/6451, 16 Azar Ave., Inqelab Sq., Tehran, Iran
| | - Ahmad Reza Shamshiri
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahrzad Pezeshki
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Islamic Azad University of Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Bahram Chahardouli
- Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Molouk Hadjibabaie
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, PO Box 14155/6451, 16 Azar Ave., Inqelab Sq., Tehran, Iran.
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zahra Jahangard-Rafsanjani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, PO Box 14155/6451, 16 Azar Ave., Inqelab Sq., Tehran, Iran
| | - Kheirollah Gholami
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, PO Box 14155/6451, 16 Azar Ave., Inqelab Sq., Tehran, Iran
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Rajabi
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Islamic Azad University of Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Clinical Pharmacy, University Hospitals of North Midlands, Stoke-on-Trent, Staffordshire, UK
| | - Mohammad Vaezi
- Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Caltabiano R, Castrogiovanni P, Barbagallo I, Ravalli S, Szychlinska MA, Favilla V, Schiavo L, Imbesi R, Musumeci G, Di Rosa M. Identification of Novel Markers of Prostate Cancer Progression, Potentially Modulated by Vitamin D. APPLIED SCIENCES 2019; 9:4923. [DOI: 10.3390/app9224923] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Prostate cancer (PCa) is one of the most common cancers in men. The main risk factors associated with the disease include older age, family history of the disease, smoking, alcohol and race. Vitamin D is a pleiotropic hormone whose low levels are associated with several diseases and a risk of cancer. Here, we undertook microarray analysis in order to identify the genes involved in PCa. We analyzed three PCa microarray datasets, overlapped all genes significantly up-regulated, and subsequently intersected the common genes identified with the down-regulated genes transcriptome of LNCaP cells treated with 1α,25(OH)2D3, in order to identify the common genes involved in PCa and potentially modulated by Vitamin D. The analysis yielded 43 genes potentially involved in PCa and significantly modulated by Vitamin D. Noteworthy, our analysis showed that six genes (PRSS8, SOX4, SMYD2, MCCC2, CCNG2 and CD2AP) were significantly modulated. A Pearson correlation analysis showed that five genes out of six (SOX4 was independent), were statistically correlated with the gene expression levels of KLK3, and with the tumor percentage. From the outcome of our investigation, it is possible to conclude that the genes identified by our analysis are associated with the PCa and are potentially modulated by the Vitamin D.
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Affiliation(s)
- Rosario Caltabiano
- Department G.F. Ingrassia, Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Paola Castrogiovanni
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Ignazio Barbagallo
- Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Silvia Ravalli
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Marta Anna Szychlinska
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Vincenzo Favilla
- Department of Surgery, Urology Section, University of Catania, 95123 Catania, Italy
| | - Luigi Schiavo
- Obesity Unit, CETAC Medical and Research Center, 81100 Caserta, Italy
| | - Rosa Imbesi
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Giuseppe Musumeci
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
| | - Michelino Di Rosa
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, 95123 Catania, Italy
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Therapeutic targets of vitamin D receptor ligands and their pharmacokinetic effects by modulation of transporters and metabolic enzymes. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2019. [DOI: 10.1007/s40005-019-00429-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Timar A, Saberi-Karimian M, Ghazizadeh H, Reza Parizadeh SM, Sabbaghzadeh R, Emadzadeh M, Eshaghi F, Tavallaie S, Ferns GA, Ghayour-Mobarhan M. Evaluation of the serum prooxidant-antioxidant balance before and after vitamin D supplementation in adolescent Iranian girls. Adv Med Sci 2019; 64:174-180. [PMID: 30710882 DOI: 10.1016/j.advms.2018.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 09/25/2018] [Accepted: 10/31/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE Oxidative stress is caused by an imbalance between the antioxidant defenses and pro-oxidant production in favor of pro-oxidant production. Vitamin D has the potential for both pro- and anti-oxidative effects. The aim of this study was to assess the effect of high dose vitamin D supplementation on the prooxidant-antioxidant balance (PAB) in Iranian girls attending High School. MATERIALS AND METHODS A total of 464 girls aged 12-18 years were asked to take vitamin D capsules containing 50000IU vitamin D3 once a week for a period of 9 weeks. All variables were determined at baseline and after 9 weeks of intervention. Fasting blood samples were taken from all subjects. The serum levels of 25OHD were measured using an electrochemiluminescence method. Serum PAB levels were determined using an ELISA reader at a wavelength of 450 nm. RESULTS Vitamin D supplementation was associated with an increase in serum PAB (P < 0.001) and a reduction in serum LDL-C (P < 0.001), total cholesterol (P < 0.001) and HDL-C (P < 0.01) serum levels in Iranian adolescent girls. The results obtained from the current study show that there were significant improvements in weight (P < 0.001), BMI (P < 0.001) and FBG (P = 0.02) in adolescent girls who had 50-74.9 nmol/L serum 25OHD levels compared to <50 nmol/L ones after the vitamin D supplementation. There was no significant association between the serum PAB and all biochemical factors (P > 0.05 for all variables). CONCLUSIONS The results showed that vitamin D supplementation has increased the PAB levels in teenage girls.
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Salehi-Tabar R, Memari B, Wong H, Dimitrov V, Rochel N, White JH. The Tumor Suppressor FBW7 and the Vitamin D Receptor Are Mutual Cofactors in Protein Turnover and Transcriptional Regulation. Mol Cancer Res 2019; 17:709-719. [DOI: 10.1158/1541-7786.mcr-18-0991] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/05/2018] [Accepted: 12/21/2018] [Indexed: 11/16/2022]
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Fathi N, Ahmadian E, Shahi S, Roshangar L, Khan H, Kouhsoltani M, Maleki Dizaj S, Sharifi S. Role of vitamin D and vitamin D receptor (VDR) in oral cancer. Biomed Pharmacother 2018; 109:391-401. [PMID: 30399574 DOI: 10.1016/j.biopha.2018.10.102] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/18/2018] [Accepted: 10/20/2018] [Indexed: 12/14/2022] Open
Abstract
Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Vitamin D executes its functions by interacting with the vitamin D receptor (VDR), both in healthy and diseased individuals, including oral cancer. This review discusses the role of vitamin D and VDR on tumorigenesis, emphasizing on oral cancer. Furthermore, regulation of VDR expression, mechanisms of anticancer effects of calcitriol, oral cancer chemoresistance and its relation with VDR and polymorphisms of VDR gene will be discussed. The manuscript is prepared mainly using the information collected from PubMed and MEDLINE.
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Affiliation(s)
- Nazanin Fathi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cells Research Center, Tabriz University of Medical Sciences, Iran
| | - Elham Ahmadian
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahriar Shahi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Stem Cells Research Center, Tabriz University of Medical Sciences, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali khan university, Mardan, 23200, Pakistan
| | - Maryam Kouhsoltani
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. PLoS One 2018; 13:e0202272. [PMID: 30107003 PMCID: PMC6091939 DOI: 10.1371/journal.pone.0202272] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 07/30/2018] [Indexed: 12/21/2022] Open
Abstract
Purpose Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. Patients and methods Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. Results The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70–0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63–0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. Conclusion Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.
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Without 1α-hydroxylation, the gene expression profile of 25(OH)D 3 treatment overlaps deeply with that of 1,25(OH) 2D 3 in prostate cancer cells. Sci Rep 2018; 8:9024. [PMID: 29899561 PMCID: PMC5998076 DOI: 10.1038/s41598-018-27441-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 06/04/2018] [Indexed: 12/18/2022] Open
Abstract
Recently, the antiproliferative action of 1,25(OH)2D3 (1,25D3), an active metabolite of vitamin D3, in the management of prostate cancer has been argued rigorously. In this study, we found that at a physiological concentration, 25(OH)D3 (25D3), the precursor of 1,25D3 and an inactive form of vitamin D because of its much weaker binding activity to the vitamin D receptor (VDR) compared with 1,25D3, had a gene expression profile similar to that of 1,25D3 in prostate cancer LNCaP cells. By immunocytochemistry, western blotting, and CYP27B1 and/or VDR knockdown by small interfering RNAs, we found that 10−7 M 25D3, which is within its uppermost physiological concentration in the bloodstream, induced VDR nuclear import and robustly activated its target genes in the virtual absence of CYP27B1 expression. Comprehensive microarray analyses verified 25D3 bioactivity, and we found that 25D3 target gene profiles largely matched those of 1,25D3, while the presence a small subset of 25D3- or 1,25D3-specific target genes was not excluded. These results indicated that 25D3 shares bioactivity with 1,25D3 without conversion to the latter. Metallothionein 2A was identified as a 1,25D3-specific repressive target gene, which might be a prerequisite for 1,25D3, but not 25D3, to exert its anti-proliferative action in LNCaP cells.
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Jeon SM, Shin EA. Exploring vitamin D metabolism and function in cancer. Exp Mol Med 2018; 50:1-14. [PMID: 29657326 PMCID: PMC5938036 DOI: 10.1038/s12276-018-0038-9] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/12/2017] [Indexed: 12/12/2022] Open
Abstract
Vitamin D, traditionally known as an essential nutrient, is a precursor of a potent steroid hormone that regulates a broad spectrum of physiological processes. In addition to its classical roles in bone metabolism, epidemiological, preclinical, and cellular research during the last decades, it revealed that vitamin D may play a key role in the prevention and treatment of many extra-skeletal diseases such as cancer. Vitamin D, as a prohormone, undergoes two-step metabolism in liver and kidney to produce a biologically active metabolite, calcitriol, which binds to the vitamin D receptor (VDR) for the regulation of expression of diverse genes. In addition, recent studies have revealed that vitamin D can also be metabolized and activated through a CYP11A1-driven non-canonical metabolic pathway. Numerous anticancer properties of vitamin D have been proposed, with diverse effects on cancer development and progression. However, accumulating data suggest that the metabolism and functions of vitamin D are dysregulated in many types of cancer, conferring resistance to the antitumorigenic effects of vitamin D and thereby contributing to the development and progression of cancer. Thus, understanding dysregulated vitamin D metabolism and function in cancer will be critical for the development of promising new strategies for successful vitamin D-based cancer therapy.
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Affiliation(s)
- Sang-Min Jeon
- College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea.
- Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea.
| | - Eun-Ae Shin
- College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea
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Kulling PM, Olson KC, Olson TL, Hamele CE, Carter KN, Feith DJ, Loughran TP. Calcitriol-mediated reduction in IFN-γ output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation. J Steroid Biochem Mol Biol 2018; 177:140-148. [PMID: 28736298 PMCID: PMC5775933 DOI: 10.1016/j.jsbmb.2017.07.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023]
Abstract
Constitutively activated STAT1 and elevated IFN-γ are both characteristic of T cell large granular lymphocytic leukemia (T-LGLL), a rare incurable leukemia with clonal expansion of cytotoxic T cells due to defective apoptosis. Interferon gamma (IFN-γ) is an inflammatory cytokine that correlates with worse progression and symptomology in multiple autoimmune diseases and cancers. In canonical IFN-γ-STAT1 signaling, IFN-γ activates STAT1, a transcription factor, via phosphorylation of tyrosine residue 701 (p-STAT1). p-STAT1 then promotes transcription of IFN-γ, creating a positive feedback loop. We previously found that calcitriol treatment of the TL-1 cell line, a model of T-LGLL, significantly decreased IFN-γ secretion and p-STAT1 while increasing the vitamin D receptor (VDR) protein. Here we further explore these observations. Using TL-1 cells, IFN-γ decreased starting at 4h following calcitriol treatment, with a reduction in the intracellular and secreted protein levels as well as the mRNA content. A similar reduction in IFN-γ transcript levels was observed in primary T-LGLL patient peripheral blood mononuclear cells (PBMCs). p-STAT1 inhibition followed a similar temporal pattern and VDR upregulation inversely correlated with IFN-γ levels. Using EB1089 and 25(OH)D3, which have high or low affinity for VDR, respectively, we found that the decrease in IFN-γ correlated with the ability of EB1089, but not 25(OH)D3, to upregulate VDR. However, both compounds inhibited p-STAT1; thus the reduction of p-STAT1 is not solely responsible for IFN-γ inhibition. Conversely, cells treated with VDR siRNA exhibited decreased basal IFN-γ production upon VDR knockdown in a dose-dependent manner. Calcitriol treatment upregulated VDR and decreased IFN-γ regardless of initial VDR knockdown efficiency, strengthening the connection between VDR upregulation and IFN-γ reduction. Our findings suggest multiple opportunities to further explore the clinical relevance of the vitamin D pathway and the potential role for vitamin D supplementation in T-LGLL.
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Affiliation(s)
- Paige M Kulling
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA; Department of Pathology, University of Virginia, Charlottesville, VA, 29908, USA
| | - Kristine C Olson
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA
| | - Thomas L Olson
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA
| | - Cait E Hamele
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA
| | - Kathryn N Carter
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA
| | - David J Feith
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA
| | - Thomas P Loughran
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, 29908, USA; Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, 29908, USA.
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Hoan NX, Tong HV, Song LH, Meyer CG, Velavan TP. Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review. World J Gastroenterol 2018; 24:445-460. [PMID: 29398866 PMCID: PMC5787780 DOI: 10.3748/wjg.v24.i4.445] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/08/2018] [Accepted: 01/16/2018] [Indexed: 02/06/2023] Open
Abstract
The secosteroid hormone vitamin D has, in addition to its effects in bone metabolism also functions in the modulation of immune responses against infectious agents and in inhibiting tumorigenesis. Thus, deficiency of vitamin D is associated with several malignancies, but also with a plethora of infectious diseases. Among other communicable diseases, vitamin D deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B and C viruses (HBV, HCV) and high prevalence of vitamin D deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infection are found worldwide. Several studies have assessed the effects of vitamin D supplementation on the sustained virological response (SVR) to interferon (IFN) plus ribavirin (RBV) therapy in HBV and HCV infection. In these studies, inconsistent results were reported. This review addresses general aspects of vitamin D deficiency and, in particular, the significance of vitamin D hypovitaminosis in the outcome of HBV- and HCV-related chronic liver diseases. Furthermore, current literature was reviewed in order to understand the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients.
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Affiliation(s)
- Nghiem Xuan Hoan
- Institute of Clinical Infectious Diseases, 108 Military Central Hospital, Hanoi 10004, Vietnam
- Molecular Genetics of Infectious Diseases, Institute of Tropical Medicine, University of Tübingen, Tübingen 72074, Germany
- Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
| | - Hoang Van Tong
- Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Hanoi 10004, Vietnam
| | - Le Huu Song
- Institute of Clinical Infectious Diseases, 108 Military Central Hospital, Hanoi 10004, Vietnam
- Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
| | - Christian G Meyer
- Molecular Genetics of Infectious Diseases, Institute of Tropical Medicine, University of Tübingen, Tübingen 72074, Germany
- Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
- Medical Faculty, Duy Tan University, Da Nang, Vietnam
| | - Thirumalaisamy P Velavan
- Molecular Genetics of Infectious Diseases, Institute of Tropical Medicine, University of Tübingen, Tübingen 72074, Germany
- Vietnamese-German Center of Medical Research (VG-CARE), Hanoi 10004, Vietnam
- Medical Faculty, Duy Tan University, Da Nang, Vietnam
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Xiao TT, Li X, Feng JL, Li Y. Combined effects of aspirin and vitamin D3 on two OSCC cell lines: a preliminary study. Biotechnol Lett 2018; 40:551-559. [PMID: 29349624 DOI: 10.1007/s10529-018-2508-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 01/08/2018] [Indexed: 11/26/2022]
Abstract
OBJECTIVES We evaluated the potential effects of aspirin combined with vitamin D3 on cell proliferation and apoptosis in oral cancer cells. RESULTS Compared to the untreated control or individual drug, the combinations of aspirin and vitamin D3 significantly decreased the rates of cell proliferation by CCK-8 assay, and caused higher rates of cell apoptosis in both CAL-27 and SCC-15 cells by Annexin V-FITC apoptosis assay and flow cytometry. Remarkably, the combined treatment with aspirin and vitamin D3 significantly suppressed the expression of Bcl-2 protein and p-Erk1/2 protein, examined by western blot analysis. CONCLUSIONS Our study demonstrates that aspirin and vitamin D3 have biological activity against two human OSCC cell lines and their activity is synergistic or additive when two drugs used in combination with therapeutic concentrations. The combination of aspirin and vitamin D3 may be an effective approach for inducing cell death in OSCC.
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Affiliation(s)
- Ting-Ting Xiao
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Oral Disease and Biomedical Sciences, Chongqing, People's Republic of China
| | - Xian Li
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People's Republic of China
| | - Jia-Li Feng
- Chongqing Key Laboratory of Oral Disease and Biomedical Sciences, Chongqing, People's Republic of China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People's Republic of China
| | - Yong Li
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
- Chongqing Key Laboratory of Oral Disease and Biomedical Sciences, Chongqing, People's Republic of China.
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People's Republic of China.
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Boisen IM, Bøllehuus Hansen L, Mortensen LJ, Lanske B, Juul A, Blomberg Jensen M. Possible influence of vitamin D on male reproduction. J Steroid Biochem Mol Biol 2017; 173:215-222. [PMID: 27693423 DOI: 10.1016/j.jsbmb.2016.09.023] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 09/22/2016] [Accepted: 09/28/2016] [Indexed: 01/08/2023]
Abstract
Vitamin D is a versatile signaling molecule with an established role in the regulation of calcium homeostasis and bone health. In recent years the spectrum of vitamin D target organs has expanded and a reproductive role is supported by the presence of the vitamin D receptor (VDR) and the vitamin D metabolizing enzymes in the gonads, reproductive tract, and human spermatozoa. Interestingly, expression levels of VDR and the vitamin D inactivating enzyme CYP24A1 in human spermatozoa serve as positive predictive markers of semen quality and are higher expressed in spermatozoa from normal than infertile men. VDR mediates a non-genomic increase in intracellular calcium concentration, sperm motility, and induces the acrosome reaction. Furthermore, functional animal model studies have shown that vitamin D is important for sex steroid production, estrogen signaling, and semen quality. Cross-sectional clinical studies have supported the notion of a positive association between serum 25-hydroxyvitamin D (25-OHD) level and semen quality in both fertile and infertile men. However, it remains to be determined whether this association reflects a causal effect. The VDR is ubiquitously expressed and activated vitamin D is a regulator of insulin, aromatase, and osteocalcin. Hence, it is plausible that the influence of vitamin D on gonadal function may be mediated indirectly through other vitamin D regulated endocrine factors. Recent studies have indicated that vitamin D supplementation may be beneficial for couples in need of assisted reproductive techniques as high serum vitamin D levels were found to be associated with a higher chance of achieving pregnancy. Randomized clinical trials are needed to determine whether systemic changes in vitamin D metabolites can influence semen quality, fertility, and sex steroid production in infertile men. In this review known and possible future implications of vitamin D in human male reproduction function will be discussed.
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Affiliation(s)
- Ida Marie Boisen
- University Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, USA
| | - Lasse Bøllehuus Hansen
- University Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, USA
| | - Li Juel Mortensen
- University Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, USA
| | - Beate Lanske
- Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, USA
| | - Anders Juul
- University Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Martin Blomberg Jensen
- University Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, USA.
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Badfar G, Shohani M, Mansouri A, Soleymani A, Azami M. Vitamin D status in Iranian pregnant women and newborns: a systematic review and meta-analysis study. Expert Rev Endocrinol Metab 2017; 12:379-389. [PMID: 30058894 DOI: 10.1080/17446651.2017.1365596] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Vitamin D deficiency is a common health problem worldwide. The present study was conducted to assess the vitamin D status in Iranian pregnant women and newborns. METHODS A systematic review was conducted following PRISMA guidelines. The Scopus, PubMed, Science Direct, Cochrane, Web of Science, CINAHL, Magiran, Iranmedex, SID, Medlib, IranDoc databases, and Google Scholar were searched until 2017. The data were combined using random effects model. p < 0.05 was considered significant. RESULTS In 23 studies including 6,127 Iranian pregnant women were eligible for inclusion. The prevalence of vitamin D deficiency based on cutoff points of 10, 20, and 30 ng/ml was estimated to be 42.42% (95%CI: 26.90-57.93), 55.84% (95%CI: 31.75-79.93) and 80.82% (95%CI: 71.20-90.45), respectively. The mean 25-hydroxyvitamin D [25(OH)D] concentration was estimated to be 15.69 ng/ml (95%CI: 14.39-17.00) in pregnant women. The mean 25(OH)D concentration was estimated to be 14.97 ng/ml (95% CI: 10.63-19.31) in Iranian newborns. The difference in mean 25(OH)D concentration between pregnant women and their newborns was significant (p = 0.0002). CONCLUSIONS Vitamin D status in Iranian pregnant women and newborns are critical. Therefore, paying attention to the issue of vitamin D deficiency in this group should be a health priority in Iran.
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Affiliation(s)
- Gholamreza Badfar
- a Department of Pediatrics , Behbahan Faculty of Medical Sciences , Behbahan , Iran
| | - Masoumeh Shohani
- b Department of Nursing, Faculty of Allied Medical Sciences , Ilam University of Medical Sciences , Ilam , Iran
| | - Akram Mansouri
- c School of Nursing and Midwifery , Ahvaz jundishapour university of Medical science , Ahvaz , Iran
| | - Ali Soleymani
- d Faculty of Medicine , Dezful University of Medical Sciences , Dezful , Iran
| | - Milad Azami
- e Student Research Committee , Ilam University of Medical Sciences , Ilam , Iran
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Abstract
Vitamin D exerts its canonical roles on the musculoskeletal system and in the calcium/phosphorus homeostasis. In the last years, increasing evidences suggested several extra-skeletal actions of this hormone, indicating that vitamin D may produce effects in almost all the body tissues. These are mediated by the presence of vitamin D receptor (VDR) and thanks to the presence of the 1-α-hydroxylase, the protein that converts the 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin (calcitriol). Several studies evaluated the possible role of vitamin D in the pathogenesis of thyroid diseases, and this review will focus on the available data of the literature evaluating the association between vitamin D and thyroid function, vitamin D and autoimmune thyroid diseases, including Hashimoto's thyroiditis, Graves' disease and post-partum thyroiditis, and vitamin D and thyroid cancer.
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Affiliation(s)
- Immacolata Cristina Nettore
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II", Via S. Pansini, 5, 80131, Napoli, Italy
| | - Luigi Albano
- Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli "Federico II", Napoli, Italy
| | - Paola Ungaro
- Istituto di Endocrinologia ed Oncologia Sperimentale del CNR (IEOS-CNR) "G. Salvatore", Napoli, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II", Via S. Pansini, 5, 80131, Napoli, Italy
| | - Paolo Emidio Macchia
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II", Via S. Pansini, 5, 80131, Napoli, Italy.
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Segovia-Mendoza M, Díaz L, Prado-Garcia H, Reginato MJ, Larrea F, García-Becerra R. The addition of calcitriol or its synthetic analog EB1089 to lapatinib and neratinib treatment inhibits cell growth and promotes apoptosis in breast cancer cells. Am J Cancer Res 2017; 7:1486-1500. [PMID: 28744399 PMCID: PMC5523030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 06/01/2017] [Indexed: 06/07/2023] Open
Abstract
In breast cancer the use of small molecule inhibitors of tyrosine kinase activity of the ERBB family members improves survival thus represents a valuable therapeutic strategy. The addition of calcitriol, the most active metabolite of vitamin D, or some of its analogs, to conventional anticancer drugs, including tyrosine kinase inhibitors (TKIs), has shown an increased effect on the inhibition of cancer cell growth. In this work, we have evaluated the effects and the mechanism of action of the combination of calcitriol or its analog EB1089 with lapatinib or neratinib on EGFR and/or HER2 positive breast cancer cell lines. Lapatinib, neratinib, calcitriol and EB1089 inhibited breast cancer cell proliferation in a concentration-dependent manner. Addition of calcitriol or EB1089 to TKIs treatment induced more effective inhibiting effect on cell growth and AKT and MAPK phosphorylation than all compounds alone. The combined treatments incremented also the expression of active caspase 3 and induced cell death in two and three-dimensional cell culture and significantly inhibited anchorage-independent colony formation. Our results suggest that the addition of calcitriol or its analog EB1089 to conventional targeted therapies, including lapatinib or neratinib might be of benefit to patients with breast cancer, particularly those with an EGFR and/or HER2 positive phenotype.
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Affiliation(s)
- Mariana Segovia-Mendoza
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránVasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan 14080, México, Ciudad de México
| | - Lorenza Díaz
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránVasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan 14080, México, Ciudad de México
| | - Heriberto Prado-Garcia
- Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”Calzada de Tlalpan 4502, Belisario Domínguez Sección XVI, Tlalpan 14080, México, Ciudad de México
| | - Mauricio J Reginato
- Department of Biochemistry and Molecular Biology, College of Medicine, Drexel UniversityPhiladelphia, PA, USA
| | - Fernando Larrea
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránVasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan 14080, México, Ciudad de México
| | - Rocío García-Becerra
- Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránVasco de Quiroga No. 15, Belisario Domínguez Sección XVI, Tlalpan 14080, México, Ciudad de México
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Vora L, V G S, Vavia P. Zero order controlled release delivery of cholecalciferol from injectable biodegradable microsphere: In-vitro characterization and in-vivo pharmacokinetic studies. Eur J Pharm Sci 2017. [PMID: 28629804 DOI: 10.1016/j.ejps.2017.06.027] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Poly(lactic-co-glycolic acid) microspheres loaded with cholecalciferol (CL), more bioactive form of vitamin D was developed as an injectable controlled drug release system and was evaluated for its feasibility of once a month delivery. The CL loaded microspheres (CL-MS) were prepared by simple oil in water (O/W) emulsion-solvent evaporation technique incorporated with a stabilizer, Tocopherol Succinate (TS). Different formulation as well as process parameters were investigated namely concentration of emulsifier, concentration of stabilizer and drug: polymer mass ratios. The prepared CL-MS were evaluated for particle size, drug loading, in-vitro drug release and in-vivo pharmacokinetics in rats. The optimized formulation was found to have a mean particle size of 28.62±0.26μm, Encapsulation Efficiency (EE) of 94.4±5.4% and drug loading of 5.19±0.29% with CL:TS ratio of 2:1. It was found that the EE drastically decreased (26±5.9%) in the absence of stabilizer (TS) indicating its role in stabilization of CL during formulation. DSC and XRD studies indicated that CL existed in an amorphous structure in the polymer matrix. SEM of the CL-MS revealed the spherical morphology and confirmed the particle size. In-vitro release showed that the CL release from CL-MS followed near zero-order drug release kinetics over nearly 1month. In-vivo pharmacokinetic study of CL-MS showed higher t1/2 (239±27.5h) compared to oily CL depot (32.7±4.8h) with sustained release of CL plasma concentration for 1month. The labile CL could thus be effectively encapsulated and protected against degradation during microspheres formulation, storage and release in presence of stabilizer. This novel CL loaded PLGA MS is stable and may have great potential for clinical use.
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Affiliation(s)
- Lalit Vora
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act - 1956, Elite Status and Center of Excellence, Govt. of Maharashtra, Mumbai 400 019, India
| | - Sita V G
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act - 1956, Elite Status and Center of Excellence, Govt. of Maharashtra, Mumbai 400 019, India
| | - Pradeep Vavia
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act - 1956, Elite Status and Center of Excellence, Govt. of Maharashtra, Mumbai 400 019, India.
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Lai SH, Liao SL, Tsai MH, Hua MC, Chiu CY, Yeh KW, Yao TC, Huang JL. Low cord-serum 25-hydroxyvitamin D levels are associated with poor lung function performance and increased respiratory infection in infancy. PLoS One 2017; 12:e0173268. [PMID: 28267792 PMCID: PMC5340372 DOI: 10.1371/journal.pone.0173268] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 02/17/2017] [Indexed: 11/20/2022] Open
Abstract
Background Perinatal vitamin D deficiency is associated with a higher risk of wheezing in childhood. However, the relationship between vitamin D levels and lung function in infancy has not been investigated. The aim of this study was to investigate the impact of perinatal vitamin D levels on respiratory function and disease outcome in infancy. Materials and methods Full-term infants without any chronic diseases or major anomalies were enrolled in the Prediction of Allergies in Taiwanese Children cohort study. Maternal and cord blood were collected for determining the 25(OH)D level. Questionnaires were recorded at birth and 6 months of age. Infant lung function, including tidal breathing analysis, respiratory mechanics, and forced tidal expiration, was tested at 6 months of age. Results A total of 122 mother—infant pairs were enrolled in this study, and 71 infants underwent lung function testing at 6 months of age. 25(OH)D levels in maternal and cord serum were highly correlated (r2 = 0.457, p < 0.0001). Infants with lower cord serum 25(OH)D levels (< 13.7 ng/ml) had higher resistance of respiratory system (p < 0.01) and a higher risk of a respiratory tract infection before the age of 6 months (p < 0.01). Conclusion Although a high correlation was found between maternal and cord vitamin D levels, the effect on respiratory outcome was different. Our study is the first to show that low cord 25(OH)D levels significantly relationship with poorer lung function performance and higher likelihood of a respiratory tract infection before 6 months of age.
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Affiliation(s)
- Shen-Hao Lai
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
| | - Sui-Ling Liao
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Ming-Han Tsai
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Man-Chin Hua
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Chih-Yung Chiu
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Kuo-Wei Yeh
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
| | - Tsung-Chieh Yao
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- * E-mail: (TCY); (JLH)
| | - Jing-Long Huang
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Chang Gung University, Taoyuan, Taiwan
- Prediction of Allergies in Taiwanese Children (PATCH) Cohort Study Group, Keelung, Taiwan
- * E-mail: (TCY); (JLH)
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Liguori C, Izzi F, Mercuri NB, Romigi A, Cordella A, Tarantino U, Placidi F. Vitamin D status of male OSAS patients improved after long-term CPAP treatment mainly in obese subjects. Sleep Med 2017; 29:81-85. [DOI: 10.1016/j.sleep.2016.08.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 08/10/2016] [Accepted: 08/12/2016] [Indexed: 02/07/2023]
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La Marra F, Stinco G, Buligan C, Chiriacò G, Serraino D, Di Loreto C, Cauci S. Immunohistochemical evaluation of vitamin D receptor (VDR) expression in cutaneous melanoma tissues and four VDR gene polymorphisms. Cancer Biol Med 2017; 14:162-175. [PMID: 28607807 PMCID: PMC5444928 DOI: 10.20892/j.issn.2095-3941.2017.0020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objective : Vitamin D receptor (VDR) mediates vitamin D activity. We examined whether VDR expression in excised melanoma tissues is associated with VDR gene (VDR) polymorphisms.
Methods : We evaluated VDR protein expression (by monoclonal antibody immunostaining), melanoma characteristics, and carriage of VDR-FokI-rs2228570 (C>T),VDR-BsmI-rs1544410 (G>A),VDR-ApaI-rs7975232 (T>G), andVDR-TaqI-rs731236 (T>C) polymorphisms (by restriction fragment length polymorphism). Absence or presence of restriction site was denoted by a capital or lower letter, respectively: " F” and " f” for FokI, " B” and " b” for BsmI, " A” and " a” for ApaI, and " T” and " t” for TaqI endonuclease. Seventy-four Italian cutaneous primary melanomas (52.1±12.7 years old) were studied; 51.4% were stage I, 21.6% stage II, 13.5% stage III, and 13.5% stage IV melanomas. VDR expression was categorized as follows: 100% positivevs. <100%; over the median 20% (high VDR expression) vs. ≤20% (low VDR expression); absence vs. presence of VDR-expressing cells.
Results : Stage I melanomas, Breslow thickness of <1.00 mm, level II Clark invasion, Aa heterozygous genotype, and AaTT combined genotype were more frequent in melanomas with high vs. low VDR expression. Combined genotypes BbAA, bbAa, AATt, BbAATt, and bbAaTT were more frequent in 100% vs. <100% VDR-expressing cells. Combined genotype AATT was more frequent in melanomas lacking VDR expression (odds ratio=14.5; P=0.025). VDR expression was not associated with metastasis, ulceration, mitosis >1, regression, tumor-infiltrating lymphocytes, tumoral infiltration of vascular tissues, additional skin and non-skin cancers, and melanoma familiarity.
Conclusions : We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells. Low VDR expression in AATT carriers is a new finding that merits further study. VDR expression possibly poses implications for vitamin D supplementation against melanoma. VDR expression and VDR genotype may become precise medicinal tools for melanoma in the future.
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Affiliation(s)
- Francesco La Marra
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy
| | - Giuseppe Stinco
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy.,Dermatology Clinic, Udine University-Hospital, University of Udine, Udine 33100, Italy
| | - Cinzia Buligan
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy.,Dermatology Clinic, Udine University-Hospital, University of Udine, Udine 33100, Italy
| | - Giovanni Chiriacò
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy
| | - Diego Serraino
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy
| | - Carla Di Loreto
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy
| | - Sabina Cauci
- Department of Medical Area, School of Medicine, University of Udine, Udine 33100, Italy
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Longitudinal, observational study on associations between postoperative nutritional vitamin D supplementation and clinical outcomes in esophageal cancer patients undergoing esophagectomy. Sci Rep 2016; 6:38962. [PMID: 27958342 PMCID: PMC5154179 DOI: 10.1038/srep38962] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 11/15/2016] [Indexed: 12/14/2022] Open
Abstract
Vitamin D can exert anticancer effect beyond bone and calcium metabolism. We aimed to investigate whether postoperative vitamin D supplementation affects quality of life (QOL) and survival in esophageal cancer (EC) patients. We utilized the widely used EORTC QLQ-C30 and QLQ-OES18 to assess QOL at EC diagnosis and 24 months after surgery. Generalized estimating equations (GEEs) were used to analysis the association of vitamin D supplement use with QOL. Kaplan-Meier method and Cox regression model were used to evaluate the prognostic value of vitamin D supplementation. The notably improved QOL were found among vitamin D supplementation users compared with non-users (p < 0.05). Kaplan-Meier analysis revealed that vitamin D supplement use was significantly associated with improved disease-free survival (DFS) (p = 0.030), but not related to overall survival (OS) (p = 0.303). The multivariable analysis further demonstrated vitamin D supplement use as an independent prognostic factor for DFS (p = 0.040; HR 0.610; 95% CI 0.381-0.978). In conclusion, these results showed that vitamin D supplement use could serve as a promising intervention to enhancing QOL and prolonging DFS in EC.
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Kulling PM, Olson KC, Olson TL, Feith DJ, Loughran TP. Vitamin D in hematological disorders and malignancies. Eur J Haematol 2016; 98:187-197. [PMID: 27743385 DOI: 10.1111/ejh.12818] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2016] [Indexed: 12/13/2022]
Abstract
Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field.
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Affiliation(s)
- Paige M Kulling
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.,Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.,Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Kristine C Olson
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.,Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Thomas L Olson
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.,Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - David J Feith
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.,Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Thomas P Loughran
- University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA.,Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
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Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells. Oncotarget 2016; 7:3873-83. [PMID: 26716647 PMCID: PMC4826176 DOI: 10.18632/oncotarget.6763] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 11/28/2015] [Indexed: 01/02/2023] Open
Abstract
Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirment. We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I (Prdx I) may induce leukemia-cell differentiation. However, this concept remains to be confirmed. In this work, we identified H7 as a novel Prdx I inhibitor through virtual screening, in vitro activity assay, and surface plasmon resonance assay. Cellular thermal shift assay showed that H7 directly bound to Prdx I but not to Prdxs II–V in cells. H7 treatment also increased reactive oxygen species (ROS) level and cell differentiation in leukemia cells, as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells. The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia (APL) and primary leukemia cells apart from APL NB4 cells. Moreover, the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation. We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBPβ axis. Finally, we showed H7 treatment induced cell differentiation in an APL mouse model. All of these data confirmed that Prdx I was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx I inhibition.
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Peng W, Wang K, Zheng R, Derwahl M. 1,25 dihydroxyvitamin D3 inhibits the proliferation of thyroid cancer stem-like cells via cell cycle arrest. Endocr Res 2016; 41:71-80. [PMID: 27030645 DOI: 10.3109/07435800.2015.1037048] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND An anti-proliferative effect of vitamin D has been reported in different carcinomas, including thyroid cancer. Cancer stem cells (CSCs), a very small fraction of cancer cells, are widely believed to be responsible for cancer initiation, relapse and metastasis. OBJECTIVES We addressed the question as to whether CSCs derived from the anaplastic thyroid carcinoma cell lines SW1736, C643, HTh74 and its doxorubicin- resistant subline HTh74R are also a target of vitamin D action. METHODS The effect of calcitriol on growth of HTh74, HTh74R, SW1736 and C643 cell lines was investigated by cell viability assays. In stem-enriched cells derived from thyro-spheres cell cycle analysis and apoptotic assays were performed. Furthermore, the role of calcitriol in the formation of cancer thyro-spheres and its putative differentiation-inducing effect were analysed. RESULTS CSCs isolated as thyro-spheres from all the four anaplastic thyroid carcinoma cells expressed vitamin D receptors as did their parental cells. Calcitriol inhibited proliferation of anaplastic thyroid carcinoma cells with a more pronounced effect on doxorubicin-resistant HTh74R cells, and it significantly reduced the capacity to form stem cell-derived spheres and decreased the size of these spheres that consist of CSCs and their progenitor cells. As revealed by cell cycle analysis, calcitriol induced G2/M phase arrest in thyro-sphere cells derived cells from HTh74, HTh74R and C643 but did not affect apoptosis. Finally, calcitriol altered morphology of CSCs. CONCLUSION Calcitriol inhibited the growth of CSCs derived from anaplastic thyroid cancer cells. It may also exert a pro-differentiation effect in thyroid CSCs.
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Affiliation(s)
- Wen Peng
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Kun Wang
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Rendong Zheng
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Michael Derwahl
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
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Johnson AL, Zinser GM, Waltz SE. Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity. Oncotarget 2016; 6:16304-20. [PMID: 26008979 PMCID: PMC4599271 DOI: 10.18632/oncotarget.4059] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/22/2015] [Indexed: 01/08/2023] Open
Abstract
The Ron receptor is upregulated in human breast cancers and correlates with enhanced metastasis and reduced patient survival. Ron overexpression drives mammary tumorigenesis through direct β-catenin activation and augmented tumor cell proliferation, migration and invasion. Ron and β-catenin are also coordinately elevated in breast cancers. The vitamin D receptor (VDR) antagonizes β-catenin signaling. Herein, we examined mammary tumor onset and progression using a Ron-driven murine model of breast tumorigenesis crossed with VDR deficient mice. VDR ablation accelerated mammary tumor onset and led to tumors that exhibited a desmoplastic phenotype and enhanced metastases. Tumor levels of active β-catenin were markedly increased in the absence of VDR. In vitro, VDR activation in breast cancer cells reduced β-catenin activation and transcriptional activity leading to elevated expression of the extracellular Wnt inhibitor dickkopf-related protein 1, and a reduction in the interaction of β-catenin with the cyclin D1 promoter. Expression of a stabilized form or β-catenin ablated the protective effects of VDR activation. Collectively, these studies delineate a protective role for VDR signaling in Ron-induced mammary tumorigenesis through disruption of β-catenin activation.
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Affiliation(s)
- Abby L Johnson
- Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.,Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Glendon M Zinser
- Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.,Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Susan E Waltz
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Department of Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA
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Gocek E, Studzinski GP. DNA Repair in Despair-Vitamin D Is Not Fair. J Cell Biochem 2016; 117:1733-44. [PMID: 27122067 DOI: 10.1002/jcb.25552] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 03/24/2016] [Indexed: 02/06/2023]
Abstract
The role of vitamin D as a treatment option for neoplastic diseases, once considered to have a bright future, remains controversial. The preclinical studies discussed herein show compelling evidence that Vitamin D Derivatives (VDDs) can convert some cancer and leukemia cells to a benign phenotype, by differentiation/maturation, cell cycle arrest, or induction of apoptosis. Furthermore, there is considerable, though still evolving, knowledge of the molecular mechanisms underlying these changes. However, the attempts to clearly document that the treatment outcomes of human neoplastic diseases can be positively influenced by VDDs have been, so far, disappointing. The clinical trials to date of VDDs, alone or combined with other agents, have not shown consistent results. It is our contention, shared by others, that there were limitations in the design or execution of these trials which have not yet been fully addressed. Based on the connection between upregulation of JNK by VDDs and DNA repair, we propose a new avenue of attack on cancer cells by increasing the toxicity of the current, only partially effective, cancer chemotherapeutic drugs by combining them with VDDs. This can impair DNA repair and thus kill the malignant cells, warranting a comprehensive study of this novel concept. J. Cell. Biochem. 117: 1733-1744, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Elżbieta Gocek
- Faculty of Biotechnology, Department of Proteins Biotechnology, University of Wrocław, Joliot-Curie 14A Street, Wrocław 50-383, Poland
| | - George P Studzinski
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, 07103, New Jersey, USA
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Batai K, Murphy AB, Nonn L, Kittles RA. Vitamin D and Immune Response: Implications for Prostate Cancer in African Americans. Front Immunol 2016; 7:53. [PMID: 26941739 PMCID: PMC4761841 DOI: 10.3389/fimmu.2016.00053] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 02/04/2016] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer (PCa) is the most common cancer among men in the U.S. African American (AA) men have a higher incidence and mortality rate compared to European American (EA) men, but the cause of PCa disparities is still unclear. Epidemiologic studies have shown that vitamin D deficiency is associated with advanced stage and higher tumor grade and mortality, while its association with overall PCa risk is inconsistent. Vitamin D deficiency is also more common in AAs than EAs, and the difference in serum vitamin D levels may help explain the PCa disparities. However, the role of vitamin D in aggressive PCa in AAs is not well explored. Studies demonstrated that the active form of vitamin D, 1,25-dihydroxyvitamin D, has anti-inflammatory effects by mediating immune-related gene expression in prostate tissue. Inflammation also plays an important role in PCa pathogenesis and progression, and expression of immune-related genes in PCa tissues differs significantly between AAs and EAs. Unfortunately, the evidence linking vitamin D and immune response in relation to PCa is still scarce. This relationship should be further explored at a genomic level in AA populations that are at high risk for vitamin D deficiency and fatal PCa.
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Affiliation(s)
- Ken Batai
- Division of Urology, Department of Surgery, The University of Arizona , Tucson, AZ , USA
| | - Adam B Murphy
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA
| | - Larisa Nonn
- Department of Pathology, University of Illinois at Chicago , Chicago, IL , USA
| | - Rick A Kittles
- Division of Urology, Department of Surgery, The University of Arizona , Tucson, AZ , USA
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Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D₂ as Potential Anti-Leukemic Agents. Int J Mol Sci 2016; 17:ijms17020091. [PMID: 26840307 PMCID: PMC4783874 DOI: 10.3390/ijms17020091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 12/29/2015] [Accepted: 01/04/2016] [Indexed: 02/05/2023] Open
Abstract
Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.
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Tosunbayraktar G, Bas M, Kut A, Buyukkaragoz AH. Low serum 25(OH)D levels are assocıated to hıgher BMI and metabolic syndrome parameters in adult subjects in Turkey. Afr Health Sci 2015; 15:1161-9. [PMID: 26958017 DOI: 10.4314/ahs.v15i4.15] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the association of 25(OH)D levels with biochemical, anthropometric, and metabolic data obtained from normal and obese people. METHODS This study was carried out on 90 individuals between the ages of 18 to 63 that had various body mass indexes. Blood samples and anthropometric measurements were taken. RESULTS Waist circumferences, fat mass, LDL cholesterol levels, HDL cholesterol levels, 25(OH)D levels, and triglyceride levels were significantly different according to the body mass index groups of the participants (p<0.05). When compared to the normal body mass index group, both other groups (overweight and obese) had higher waist circumferences, triglyceride levels, LDL cholesterol levels, fasting insulin levels, HOMA-IR ratios, parathyroid hormone levels, and fat mass, and had lower 25(OH)D levels (p<0.05). The overweight group participants had higher 25(OH)D levels than the obese group, and had lower waist circumferences, fat mass, fasting insulin level, HOMA-IR ratios, and HbA1C and PTH levels than those in the obese group (p<0.05). CONCLUSION In conclusion, the mean level of 25(OH)D is very low in overweight and obese individuals and low serum 25(OH)D levels appear to be associated with obesity, visceral obesity, hypertriglyceridemia, insulin resistance, and metabolic syndrome in obese patients.
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Zardast M, Namakin K, Sharifzade G, Rezvani MR, Rahmani Y, Behrozifar S. Vitamin D Deficiency in 7 - 11 Year Old Children in Eastern Iran. INTERNATIONAL JOURNAL OF SCHOOL HEALTH 2015. [DOI: 10.17795/intjsh27749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Kurihayashi AY, Augusto RA, Escaldelai FMD, Martini LA. [Vitamin A and D status among child participants in a food supplementation program]. CAD SAUDE PUBLICA 2015; 31:531-42. [PMID: 25859720 DOI: 10.1590/0102-311x00082814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 10/31/2014] [Indexed: 11/22/2022] Open
Abstract
Vitamin A and D serum concentrations and risk factors for their deficiencies were investigated in children participating in a government-sponsored fortified milk program. The study used multivariate linear regression analysis with hierarchical selection of independent variables: socio-demographic conditions, children's health, food consumption, breastfeeding, fortified milk, exposure to sunlight, anthropometric measurements, and serum concentration of retinol and 25(OH)D. Vitamin A and vitamin D insufficiency and deficiency values were defined as < 1.05 µmol/L, < 0.7 µmol/L, < 30 ng/mL, and < 20 ng/mL, respectively. Vitamin A and D intake was inadequate. Prevalence rates for vitamin A and vitamin D insufficiency and deficiency were 19%, 6%, 82%, and 58%, respectively. Factors associated with low serum vitamin A were exclusive breastfeeding for less than 120 days, low maternal schooling, maternal unemployment, more consumers of fortified milk in the family, and low serum vitamin D. Factors associated with vitamin D deficiency were low exposure to sunlight and low serum vitamin A. Nutritional education is needed to improve children's nutritional status.
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