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Veeresh PKM, Basavaraju CG, Dallavalasa S, Anantharaju PG, Natraj SM, Sukocheva OA, Madhunapantula SV. Vitamin D3 Inhibits the Viability of Breast Cancer Cells In Vitro and Ehrlich Ascites Carcinomas in Mice by Promoting Apoptosis and Cell Cycle Arrest and by Impeding Tumor Angiogenesis. Cancers (Basel) 2023; 15:4833. [PMID: 37835527 PMCID: PMC10571758 DOI: 10.3390/cancers15194833] [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: 08/26/2023] [Revised: 09/16/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective in mitigating the cancer burden. However, the molecular mechanisms of vitamin D3 (cholecalciferol, vit-D3)-induced cancer cell death are not fully elucidated. The vit-D3 efficacy of cell death activation was assessed using breast carcinoma cell lines in vitro and a widely used Ehrlich ascites carcinoma (EAC) breast cancer model in vivo in Swiss albino mice. Both estrogen receptor-positive (ER+, MCF-7) and -negative (ER-, MDA-MB-231, and MDA-MB-468) cell lines absorbed about 50% of vit-D3 in vitro over 48 h of incubation. The absorbed vit-D3 retarded the breast cancer cell proliferation in a dose-dependent manner with IC50 values ranging from 0.10 to 0.35 mM. Prolonged treatment (up to 72 h) did not enhance vit-D3 anti-proliferative efficacy. Vit-D3-induced cell growth arrest was mediated by the upregulation of p53 and the downregulation of cyclin-D1 and Bcl2 expression levels. Vit-D3 retarded cell migration and inhibited blood vessel growth in vitro as well as in a chorioallantoic membrane (CAM) assay. The intraperitoneal administration of vit-D3 inhibited solid tumor growth and reduced body weight gain, as assessed in mice using a liquid tumor model. In summary, vit-D3 cytotoxic effects in breast cancer cell lines in vitro and an EAC model in vivo were associated with growth inhibition, the induction of apoptosis, cell cycle arrest, and the impediment of angiogenic processes. The generated data warrant further studies on vit-D3 anti-cancer therapeutic applications.
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Affiliation(s)
- Prashanth Kumar M. Veeresh
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
| | - Chaithanya G. Basavaraju
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
| | - Siva Dallavalasa
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
| | - Preethi G. Anantharaju
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
| | - Suma M. Natraj
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
| | - Olga A. Sukocheva
- Department of Hepatology, Royal Adelaide Hospital, Port Rd, Adelaide 5000, Australia;
| | - SubbaRao V. Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (P.K.M.V.); (C.G.B.); (S.D.); (P.G.A.); (S.M.N.)
- Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
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Almaghrbi H, Al-Shafai M, Al-Asmakh M, Bawadi H. Association of Vitamin D Genetic Risk Score with Noncommunicable Diseases: A Systematic Review. Nutrients 2023; 15:4040. [PMID: 37764823 PMCID: PMC10537716 DOI: 10.3390/nu15184040] [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: 08/18/2023] [Revised: 09/09/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Background and Aims: The genetic risk score (GRS) is an important tool for estimating the total genetic contribution or susceptibility to a certain outcome of interest in an individual, taking into account their genetic risk alleles. This study aims to systematically review the association between the GRS of low vitamin D with different noncommunicable diseases/markers. Methods: The article was first registered in PROSPERO CRD42023406929. PubMed and Embase were searched from the time of inception until March 2023 to capture all the literature related to the vitamin D genetic risk score (vD-GRS) in association with noncommunicable diseases. This was performed using comprehensive search terms including "Genetic Risk Score" OR "Genetics risk assessment" OR "Genome-wide risk score" AND "Vitamin D" OR 25(HO)D OR "25-hydroxyvitamin D". Results: Eleven eligible studies were included in this study. Three studies reported a significant association between vD-GRS and metabolic parameters, including body fat percentage, body mass index, glycated hemoglobin, and fasting blood glucose. Moreover, colorectal cancer overall mortality and the risk of developing arterial fibrillation were also found to be associated with genetically deprived vitamin D levels. Conclusions: This systematic review highlights the genetic contribution of low-vitamin-D-risk single nucleotides polymorphisms (SNPs) as an accumulative factor associated with different non-communicable diseases/markers, including cancer mortality and the risk of developing obesity, type 2 diabetes, and cardiovascular diseases such as arterial fibrillation.
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Affiliation(s)
- Heba Almaghrbi
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.); (M.A.-S.); (M.A.-A.)
| | - Mashael Al-Shafai
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.); (M.A.-S.); (M.A.-A.)
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar
| | - Maha Al-Asmakh
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.); (M.A.-S.); (M.A.-A.)
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar
| | - Hiba Bawadi
- Department of Human Nutrition, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Affiliation(s)
- Albert J Bredenoord
- Department of Gastroenterology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
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Seal KH, Bertenthal D, Carey E, Grunfeld C, Bikle DD, Lu CM. Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. J Gen Intern Med 2022; 37:853-861. [PMID: 34981368 PMCID: PMC8723909 DOI: 10.1007/s11606-021-07170-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/24/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND The relationship between vitamin D status and COVID-19-related clinical outcomes is controversial. Prior studies have been conducted in smaller, single-site, or homogeneous populations limiting adjustments for social determinants of health (race/ethnicity and poverty) common to both vitamin D deficiency and COVID-19 outcomes. OBJECTIVE To evaluate the dose-response relationship between continuous 25(OH)D and risk for COVID-19-related hospitalization and mortality after adjusting for covariates associated with both vitamin D deficiency and COVID-19 outcomes. DESIGN Retrospective cohort study. PATIENTS Veteran patients receiving care in US Department of Veteran Affairs (VA) health care facilities with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and a blood 25(OH)D test between February 20, 2020, and November 8, 2020, followed for up to 60 days. MAIN MEASURES Exposure was blood 25(OH)D concentration ascertained closest to and within 15 to 90 days preceding an index positive SARS-CoV-2 test. Co-primary study outcomes were COVID-19-related inpatient hospitalization requiring airborne, droplet, contact, or other isolation and mortality ascertained within 60 days of an index positive SARS-CoV-2 test. KEY RESULTS Of 4,599 veterans with a positive SARS-CoV-2 test, vitamin D deficiency (< 20 ng/mL) was identified in 665 (14.5%); 964 (21.0%) were hospitalized; and 340 (7.4%) died. After adjusting for all covariates, including race/ethnicity and poverty, there was a significant independent inverse dose-response relationship between increasing continuous 25(OH)D concentrations (from 15 to 60 ng/mL) and decreasing probability of COVID-19-related hospitalization (from 24.1 to 18.7%, p=0.009) and mortality (from 10.4 to 5.7%, p=0.001). In modeling 25(OH)D as a log-transformed continuous variable, the greatest risk for hospitalization and death was observed at lower 25(OH)D concentrations. CONCLUSIONS Continuous blood 25(OH)D concentrations are independently associated with COVID-19-related hospitalization and mortality in an inverse dose-response relationship in this large racially and ethnically diverse cohort of VA patients. Randomized controlled trials are needed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes.
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Affiliation(s)
- Karen H Seal
- San Francisco Veterans Affairs Health Care System, Integrative Health Service, San Francisco, CA, USA.
- Departments of Medicine and Psychiatry, University of California San Francisco, San Francisco, CA, USA.
| | - Daniel Bertenthal
- San Francisco Veterans Affairs Health Care System, Integrative Health Service, San Francisco, CA, USA
| | - Evan Carey
- Center of Innovation for Veteran-Centered and Value-Driven Care, VA Eastern Colorado Health Care System, Denver, CO, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Carl Grunfeld
- San Francisco Veterans Affairs Health Care System, Research Service and Division of Endocrinology and Metabolism, San Francisco, CA, USA
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Daniel D Bikle
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- San Francisco Veterans Affairs Health Care System, Division of Endocrinology and Metabolism and Dermatology, San Francisco, CA, USA
| | - Chuanyi M Lu
- Department of Laboratory Medicine, University of California San Francisco and San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
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Muchtar E, Drake MT, Leung N, Dispenzieri A, Lacy MQ, Buadi FK, Dingli D, Hayman SR, Kapoor P, Hwa YL, Fonder A, Hobbs M, Gonsalves W, Kourelis TV, Warsame R, Russell S, Go RS, Binder M, Kyle RA, Rajkumar SV, Kumar SK, Gertz MA. Hypovitaminosis D Is Prevalent in Patients With Renal AL Amyloidosis and Associated With Renal Outcome. Front Endocrinol (Lausanne) 2022; 13:891712. [PMID: 35800433 PMCID: PMC9253369 DOI: 10.3389/fendo.2022.891712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Vitamin D deficiency is common, but no data have been reported on vitamin D levels in light chain (AL) amyloidosis. PATIENTS AND METHODS In this exploratory study, stored serum samples from 173 patients with newly diagnosed AL amyloidosis were analyzed for vitamin studies which included 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and vitamin D binding protein (DBP). Measurements were made by liquid chromatography-tandem mass spectrometry. Kidney survival and overall survival (OS) were assessed in association to vitamin D status. RESULTS Cardiac and kidney involvement occurred in 69% and 63% of patients, respectively. 25(OH)D deficiency (<20 ng/mL) was seen in 56.6% of the patients and was notably found among patients with heavy proteinuria (96%), hypoalbuminemia (84.3%) and morbidly obese patients (68.3%). Heavy proteinuria (>5 gr/24-h) and vitamin D supplementation were independent predictors of 25(OH)D level on nominal multivariate regression analysis. 1,25(0H)2D deficiency was noted in 37.6% of patients and was independently associated with low eGFR and hypoalbuminemia. Progression to ESRD occurred in 23.7% of evaluable patients. Patients who progressed to ESRD had lower serum 25(OH)D and 1,25(OH)2D levels compared to those who did not progress to ESRD. On a multivariate analysis, severe 25(OH)D deficiency was an independent predictor of progression to ESRD as was renal stage, while 1,25(OH)2D deficiency was not. CONCLUSIONS Hypovitaminosis D is common in AL amyloidosis, particularly among patients with heavy proteinuria. Severe 25(OH)D deficiency at time of diagnosis predicts progression to ESRD.
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Affiliation(s)
- Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Eli Muchtar,
| | - Matthew T. Drake
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
- Department of Endocrinology and Kogod Center of Aging, Mayo Clinic College of Medicine, Rochester, MN, United States
| | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | | | - Martha Q. Lacy
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Francis K. Buadi
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | | | - Prashant Kapoor
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Yi Lisa Hwa
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Amie Fonder
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Miriam Hobbs
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Wilson Gonsalves
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | | | - Rahma Warsame
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Stephen Russell
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Ronald S. Go
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Moritz Binder
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Robert A. Kyle
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | | | - Shaji K. Kumar
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Morie A. Gertz
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
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Vitamins as Possible Cancer Biomarkers: Significance and Limitations. Nutrients 2021; 13:nu13113914. [PMID: 34836171 PMCID: PMC8622959 DOI: 10.3390/nu13113914] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/11/2022] Open
Abstract
The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.
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Bikle DD. Vitamin D regulation of and by long non coding RNAs. Mol Cell Endocrinol 2021; 532:111317. [PMID: 34015414 DOI: 10.1016/j.mce.2021.111317] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 01/08/2023]
Abstract
Two percent or less of the genome is used to transcribe mRNAs encoding proteins. Nearly all the remainder is utilized in transcribing non coding RNAs, the bulk of which are RNAs at least 200 base in length, long non coding RNAs (lncRNA). Their number is estimated to be about 28,000, but only a small fraction of lncRNAs are well characterized. That said lncRNAs have been found to regulate a very diverse array of biochemical and genomic functions. One of the transcription factors found to be regulated by and to regulate lncRNA is the vitamin D receptor (VDR). Like lncRNAs VDR is involved in the regulation of numerous biochemical and genomic processes, so it is not surprising that there would be a number of interactions between lncRNAs and VDR in their diverse functions. However, the study of these interactions is in its infancy. To date most attention has been paid to their interactions in cancer. Our own studies have focused on non melanoma skin cancers, keratinocyte carcinomas to be precise. Deletion of VDR from keratinocytes predisposes them to malignant transformation. Among a number of potential mechanisms we found that VDR deletion from these cells alters the lncRNA profile to a more oncogenic configuration, increasing the expression of well known oncogenic lncRNAs and decreasing the expression of well known tumor suppressor lncRNAs. Subsequent studies in other cancers have found similar associations between VDR and oncogenic lncRNAs with evidence of tumor specificity. To date these studies primarily reveal associations rather than causality, but causal links should be expected as research in this field continues to develop.
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Affiliation(s)
- Daniel D Bikle
- University of California, San Francisco, 1700, Owens St, San Francisco, CA, 94158, USA; San Francisco VA Medical Center, 1700, Owens St, San Francisco, CA, 94158, USA.
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Anti-Tumor Effects of Ginsenoside 20(S)-Protopanaxadiol and 1,25-Dihydroxyvitamin D3 Combination in Castration Resistant Prostate Cancer. MEDICINES 2021; 8:medicines8060028. [PMID: 34199743 PMCID: PMC8227560 DOI: 10.3390/medicines8060028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 11/16/2022]
Abstract
In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using nuclear receptor signaling. Athymic male nude mice were utilized to establish an androgen-independent human prostate cancer C4-2 cell castration-resistant prostate cancer (CRPC) xenograft model. Mice were treated orally for six weeks with 70 mg/kg aPPD administered once daily or three times per week with 4 µg/kg calcitriol or in combination or only with vehicle control. Contrary to our expectations, calcitriol treatment alone increased C4-2 tumor growth. However, the addition of calcitriol substantially increased aPPD-mediated tumor growth suppression (76% vs. 53%, combination vs. aPPD alone). The combination treatment significantly increased levels of cleaved caspase-3 apoptotic marker compared to vehicle-treated or aPPD-treated C4-2 tumors. The mechanistic elucidations indicate that tumor inhibition by the aPPD and calcitriol combination was accompanied by elevated vitamin D receptor (VDR) protein expression. In silico data suggest that aPPD weakly binds to the native LBD pocket of VDR. Interestingly, the combination of aPPD and calcitriol activated VDR at a significantly higher level than calcitriol alone and this indicates that aPPD may be an allosteric activator of VDR. Overall, aPPD and calcitriol combination significantly inhibited tumor growth in vivo with no acute or chronic toxic effects in the C4-2 xenograft CRPC nude mice. The involvement of VDR and downstream apoptotic pathways are potential mechanistic routes of antitumor effects of this combination.
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Hossain S, Liu Z, Wood RJ. Association between histone deacetylase activity and vitamin D-dependent gene expressions in relation to sulforaphane in human colorectal cancer cells. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2021; 101:1833-1843. [PMID: 32964464 DOI: 10.1002/jsfa.10797] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 05/28/2020] [Accepted: 09/23/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND It is relatively unknown as to how dietary bioactive compound sulforaphane (SFN) and vitamin D regulate gene expression in colorectal cancer. We hypothesized that a combination of SFN with vitamin D would prove beneficial in colorectal cancer. A combinatorial chemo-preventive strategy was employed to investigate the impact of SFN on chromatin remodeling in colorectal carcinoma. To understand the epigenetics-mediated changes in gene expression in response to SFN and vitamin D, Caco-2 cells were exposed for 24 h to vitamin D (100 nmol L-1 ) either alone or in combination with SFN and trichostatin A (20 and 1 μmol L-1 , respectively) at 70% confluency (proliferating) and after 13 days post-confluency (fully differentiated). Changes to VDR, CYP24A1, CYP27B1 and TRPV6 gene expressions were quantified using real-time PCR-based assays. Histone deacetylase (HDAC) inhibitor activity was assessed using HDAC I/II assay that measured global changes in acetylation status. RESULTS In differentiated Caco-2 cells, none of the genes had significant changes from D alone group. D + SFN (P = 0.99) demonstrated an opposing effect from D alone and decreased VDR expression. However, in proliferating Caco-2 cells, D + SFN (P < 0.04) increased VDR expression and decreased CYP27B1 (P < 0.01) more than D alone (P = 0.38 and 0.07, respectively). Although statistically significant, D + SFN (P = 0.01) effect on HDAC inhibitor activity was less than trichostatin A alone group (P < 0.0004) or SFN alone group (P < 0.0014). CONCLUSIONS The data suggest that colon cancer cells respond to dietary components differently under different conditions. The effect of vitamin D and SFN is selective and gene-specific in the complex multistep process of colorectal carcinogenesis in vitro. © 2020 Society of Chemical Industry.
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Affiliation(s)
| | - Zhenhua Liu
- Department of Nutrition, University of Massachusetts, Amherst, MA, USA
| | - Richard J Wood
- Department of Nutrition, University of Massachusetts, Amherst, MA, USA
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Ames BN, Grant WB, Willett WC. Does the High Prevalence of Vitamin D Deficiency in African Americans Contribute to Health Disparities? Nutrients 2021; 13:499. [PMID: 33546262 PMCID: PMC7913332 DOI: 10.3390/nu13020499] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/24/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
African Americans have higher incidence of, and mortality from, many health-related problems than European Americans. They also have a 15 to 20-fold higher prevalence of severe vitamin D deficiency. Here we summarize evidence that: (i) this health disparity is partly due to insufficient vitamin D production, caused by melanin in the skin blocking the UVB solar radiation necessary for its synthesis; (ii) the vitamin D insufficiency is exacerbated at high latitudes because of the combination of dark skin color with lower UVB radiation levels; and (iii) the health of individuals with dark skin can be markedly improved by correcting deficiency and achieving an optimal vitamin D status, as could be obtained by supplementation and/or fortification. Moderate-to-strong evidence exists that high 25-hydroxyvitamin D levels and/or vitamin D supplementation reduces risk for many adverse health outcomes including all-cause mortality rate, adverse pregnancy and birth outcomes, cancer, diabetes mellitus, Alzheimer's disease and dementia, multiple sclerosis, acute respiratory tract infections, COVID-19, asthma exacerbations, rickets, and osteomalacia. We suggest that people with low vitamin D status, which would include most people with dark skin living at high latitudes, along with their health care provider, consider taking vitamin D3 supplements to raise serum 25-hydroxyvitamin D levels to 30 ng/mL (75 nmol/L) or possibly higher.
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Affiliation(s)
- Bruce N. Ames
- Molecular and Cell Biology, Emeritus, University of California, Berkeley, CA 94720, USA;
| | - William B. Grant
- Sunlight, Nutrition and Health Research Center, San Francisco, CA 94164-1603, USA
| | - Walter C. Willett
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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11
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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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12
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Abstract
Epistemology is the main branch of philosophy that studies the nature of knowledge, but how is new knowledge created? In this perspective article, I introduce a novel method of knowledge discovery that synthesizes online findings from current and prior research. This web-based knowledge synthesis method is especially relevant in today’s information technology environment, where the research community has easy access to online interactive tools and an expansive selection of digitized peer-reviewed literature. Based on a grounded theory methodology, the innovative synthesis method presented here can be used to organize, analyze and combine concepts from an intermixed selection of quantitative and qualitative research, inferring an emerging theory or thesis of new knowledge. Novel relationships are formed when synthesizing causal theories—accordingly, this article reviews basic logical principles of associative relationships, mediators and causal pathways inferred in knowledge synthesis. I also provide specific examples from my own knowledge syntheses in the field of epidemiology. The application of this web-based knowledge synthesis method, and its unique potential to discover breakthrough knowledge, will be of interest to researchers in other areas, such as education, health, humanities, and the science, technology, engineering, and mathematics (STEM) fields.
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13
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McClorry S, Slupsky CM, Lind T, Karlsland Åkeson P, Hernell O, Öhlund I. Effectiveness of vitamin D supplementation in Swedish children may be negatively impacted by BMI and serum fructose. J Nutr Biochem 2019; 75:108251. [PMID: 31707286 DOI: 10.1016/j.jnutbio.2019.108251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 07/29/2019] [Accepted: 09/13/2019] [Indexed: 12/29/2022]
Abstract
In regions where sunlight exposure is limited, dietary vitamin D intake becomes important for maintaining status. However, Swedish children have been shown to have deficient or marginal status during the winter months even if the recommended dietary intake is met. Since low vitamin D status has been associated with several disease states, this study investigated the metabolic changes associated with improved vitamin D status due to supplementation. During the 3 winter months, 5-7-year-old children (n=170) in northern (Umeå, 63° N) and southern (Malmö, 55° N) Sweden were supplemented daily with 2 (placebo), 10 or 25 μg of vitamin D. BMI-for-age z-scores (BAZ), S-25(OH)D concentrations, insulin concentrations and the serum metabolome were assessed at baseline and follow-up. S-25(OH)D concentrations increased significantly in both supplementation groups (P<.001). Only arginine and isopropanol concentrations exhibited significant associations with improvements in S-25(OH)D. Furthermore, the extent to which S-25(OH)D increased was correlated with a combination of baseline BAZ and the change in serum fructose concentrations from baseline to follow up (P=.012). In particular, the change in S-25(OH)D concentrations was negatively correlated (P=.030) with the change in fructose concentrations for subjects with BAZ ≥0 and consuming at least 20 μg vitamin D daily. These results suggest that although the metabolic changes associated with improved vitamin D status are small, the effectiveness of dietary supplementation may be influenced by serum fructose concentrations.
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Affiliation(s)
- Shannon McClorry
- Department of Nutrition and Technology, University of California, Davis, CA, USA.
| | - Carolyn M Slupsky
- Department of Nutrition and Technology, University of California, Davis, CA, USA; Department of Food Science and Technology, University of California, Davis, CA, USA.
| | - Torbjörn Lind
- Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden,.
| | - Pia Karlsland Åkeson
- Faculty of Medicine, Department of Clinical Sciences, Pediatrics, Lund University, Malmö/Lund, Sweden.
| | - Olle Hernell
- Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden,.
| | - Inger Öhlund
- Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden,.
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14
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Abstract
Recently reported findings from major clinical trials show no cancer protection from vitamin D supplementation, and results from observational studies of vitamin D in cancer prevention are inconsistent. There is a need for new hypotheses to guide investigations of the controversies surrounding vitamin D supplementation and cancer. Bioactive vitamin D, 1,25(OH)2D, is an endocrine factor that regulates phosphate homeostasis by increasing dietary phosphate intestinal absorption. When phosphorus serum levels are high, as in hyperphosphatemia, an endocrine feedback mechanism lowers bioactive vitamin D which reduces intestinal phosphate absorption. Low vitamin D levels have been associated with cancer incidence, and tumorigenesis is associated with high levels of dysregulated phosphate in the body. In this mini-review, the author hypothesizes that hyperphosphatemia may be an intermediating factor in the association of lowered vitamin D levels and increased risk for tumorigenesis. Furthermore, this article challenges the UVB-vitamin D-cancer hypothesis which proposes that reduced cancer incidence at lower geographic latitudes is related to high levels of vitamin D from UVB exposure. The author proposes that reduced phosphorus content and availability in tropical and subtropical soil, and lower dietary phosphate intake from consumption of tropical and subtropical crops (as in the Mediterranean diet), may mediate the association of reduced cancer risk with lower latitudes.
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Affiliation(s)
- Ronald B Brown
- School of Public Health and Health Systems, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
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15
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Selected Office Based Anticancer Treatment Strategies. JOURNAL OF ONCOLOGY 2019; 2019:7462513. [PMID: 30766601 PMCID: PMC6350558 DOI: 10.1155/2019/7462513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 01/06/2019] [Indexed: 12/16/2022]
Abstract
Over the years, the treatment of patients with cancer has varied widely as much because of recent advancements in science and medicine as the philosophies that belie their use. This paper briefly describes many of the prevailing approaches in use today with an attempt to offer some perspective of how to apply these disparate methodologies so that they may be more effectively integrated, resulting in consistently better clinical responses.
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16
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Roehlen N, Doering C, Hansmann ML, Gruenwald F, Vorlaender C, Bechstein WO, Holzer K, Badenhoop K, Penna-Martinez M. Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer. Front Endocrinol (Lausanne) 2018; 9:527. [PMID: 30271381 PMCID: PMC6142903 DOI: 10.3389/fendo.2018.00527] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 08/21/2018] [Indexed: 12/23/2022] Open
Abstract
Background: Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in FOXO3a gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects. Methods: The SNP's FOXO3a rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)2D3 and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro. Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (pcorrected = pc = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (pc = 0.02 and pc = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)2D3 showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05). Conclusions: FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.
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Affiliation(s)
- Natascha Roehlen
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, Germany
- *Correspondence: Natascha Roehlen
| | - Claudia Doering
- Senckenberg Institute for Pathology, University Frankfurt, Frankfurt, Germany
| | - Martin-Leo Hansmann
- Senckenberg Institute for Pathology, University Frankfurt, Frankfurt, Germany
| | - Frank Gruenwald
- Department of Nuclear Medicine, University Frankfurt, Frankfurt, Germany
| | | | | | - Katharina Holzer
- Section of Endocrine Surgery, Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Klaus Badenhoop
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, Germany
| | - Marissa Penna-Martinez
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, Germany
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17
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Vitamin D in Household Food Supplies of Homebound Older Adults Receiving Home-Delivered Meals. TOP CLIN NUTR 2017. [DOI: 10.1097/tin.0000000000000121] [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]
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18
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Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC, Jetten AM. Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR and inverse agonists on RORα and RORγ. J Steroid Biochem Mol Biol 2017; 173:42-56. [PMID: 27693422 PMCID: PMC5373926 DOI: 10.1016/j.jsbmb.2016.09.024] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 09/17/2016] [Accepted: 09/28/2016] [Indexed: 02/07/2023]
Abstract
The classical pathway of vitamin D activation follows the sequence D3→25(OH)D3→1,25(OH)2D3 with the final product acting on the receptor for vitamin D (VDR). An alternative pathway can be started by the action of CYP11A1 on the side chain of D3, primarily producing 20(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3 and 17,20,23(OH)3D3. Some of these metabolites are hydroxylated by CYP27B1 at C1α, by CYP24A1 at C24 and C25, and by CYP27A1 at C25 and C26. The products of these pathways are biologically active. In the epidermis and/or serum or adrenals we detected 20(OH)D3, 22(OH)D3, 20,22(OH)2D3, 20,23(OH)2D3, 17,20,23(OH)3D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,22(OH)3D3, 20,24(OH)2D3, 1,20,24(OH)3D3, 20,25(OH)2D3, 1,20,25(OH)3D3, 20,26(OH)2D3 and 1,20,26(OH)3D3. 20(OH)D3 and 20,23(OH)2D3 are non-calcemic, while the addition of an OH at C1α confers some calcemic activity. Molecular modeling and functional assays show that the major products of the pathway can act as "biased" agonists for the VDR with high docking scores to the ligand binding domain (LBD), but lower than that of 1,25(OH)2D3. Importantly, cell based functional receptor studies and molecular modeling have identified the novel secosteroids as inverse agonists of both RORα and RORγ receptors. Specifically, they have high docking scores using crystal structures of RORα and RORγ LBDs. Furthermore, 20(OH)D3 and 20,23(OH)2D3 have been tested in a cell model that expresses a Tet-on RORα or RORγ vector and a RORE-LUC reporter (ROR-responsive element), and in a mammalian 2-hybrid model that test interactions between an LBD-interacting LXXLL-peptide and the LBD of RORα/γ. These assays demonstrated that the novel secosteroids have ROR-antagonist activities that were further confirmed by the inhibition of IL17 promoter activity in cells overexpressing RORα/γ. In conclusion, endogenously produced novel D3 hydroxy-derivatives can act both as "biased" agonists of the VDR and/or inverse agonists of RORα/γ. We suggest that the identification of large number of endogenously produced alternative hydroxy-metabolites of D3 that are biologically active, and of possible alternative receptors, may offer an explanation for the pleiotropic and diverse activities of vitamin D, previously assigned solely to 1,25(OH)2D3 and VDR.
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MESH Headings
- Animals
- Cholesterol Side-Chain Cleavage Enzyme/metabolism
- Humans
- Hydroxycholecalciferols/metabolism
- Hydroxycholecalciferols/pharmacology
- Models, Molecular
- Nuclear Receptor Subfamily 1, Group F, Member 1/agonists
- Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/agonists
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Receptors, Calcitriol/agonists
- Receptors, Calcitriol/metabolism
- Vitamins/metabolism
- Vitamins/pharmacology
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Affiliation(s)
- Andrzej T Slominski
- Department of Dermatology, USA; Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, USA; Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, 35249, USA.
| | | | - Judith V Hobrath
- Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | | | - Edith K Y Tang
- School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia
| | - Elaine W Tieu
- School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia
| | - Wei Li
- Department of Pharmaceutical Sciences University of Tennessee HSC, Memphis, TN 38163, USA
| | - Robert C Tuckey
- School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia
| | - Anton M Jetten
- Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
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19
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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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20
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Teegarden MD, Campbell AR, Cooperstone JL, Tober KL, Schwartz SJ, Oberyszyn TM. 25-Hydroxyvitamin D 3 and its C-3 epimer are elevated in the skin and serum of Skh-1 mice supplemented with dietary vitamin D 3. Mol Nutr Food Res 2017; 61. [PMID: 28589636 DOI: 10.1002/mnfr.201700293] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/23/2017] [Accepted: 05/24/2017] [Indexed: 11/05/2022]
Abstract
SCOPE UV exposure is a risk factor for keratinocyte carcinoma (KC) while critical for endogenous vitamin D production. We investigated dietary modulation of skin and serum 25-hydroxyvitamin D3 (25OHD3 ) and its C-3 epimer (C3epi) in a mouse model of KC. C3epi is an under-investigated metabolite of vitamin D with respect to its biological implications. METHODS AND RESULTS Male and female Skh-1 mice were supplemented with 25, 150 or 1000 IU/kg diet vitamin D3 for 25 weeks, with some exposed to UV light. Skin and serum vitamin D metabolites were quantitated using HPLC-MS/MS (n = 3 per dose/sex/UV treatment). Serum and skin 25OHD3 and C3epi significantly increased with dose (P<0.0001), but with different response patterns. UV exposure significantly attenuated serum, but not skin, levels of both metabolites (P<0.001, P = 0.0287), while up-regulating expression of renal Cyp24a1 (P < 0.01). A dose by sex interaction trended toward significance with serum and skin levels of C3epi, wherein male mice attained higher levels of C3epi with higher dietary vitamin D3 . This reflected a similar, but non-significant pattern in average tumor size. CONCLUSION The complex relationship between vitamin D and KC requires further investigation. This study provides insight into modulation of local and systemic vitamin D status with dietary supplementation.
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Affiliation(s)
- Matthew D Teegarden
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA
| | - Amanda R Campbell
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jessica L Cooperstone
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA
| | - Kathleen L Tober
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Steven J Schwartz
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA
| | - Tatiana M Oberyszyn
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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21
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Shimizu T, Kamel WA, Yamaguchi-Iwai S, Fukuchi Y, Muto A, Saya H. Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response. Cancer Sci 2017. [PMID: 28643892 PMCID: PMC5581526 DOI: 10.1111/cas.13304] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)-approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin D1, activation of p38 MAPK, and intracellular production of reactive oxygen species (ROS). Knockdown of Atf4 or Ddit3 restored cell viability after calcitriol treatment, indicating that the ER stress response was indeed responsible for the anti-proliferative effect in AXT cells. Notably, the ER stress response was induced to a lesser extent in human osteosarcoma than in AXT cells, consistent with the weaker suppressive effect on cell growth in the human cells. Thus, the magnitude of ER stress induced by calcitriol might be an index of its anti-osteosarcoma effect. Although mice treated with calcitriol exhibited weight loss and elevated serum calcium levels, a single dose was sufficient to decrease osteosarcoma tumor size in vivo. Our findings suggest that calcitriol holds therapeutic potential for treatment of osteosarcoma, assuming that techniques to diminish its toxicity could be established. In addition, our results show that calcitriol could still be safely administered to osteosarcoma patients for its original purposes, including treatment of osteoporosis.
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Affiliation(s)
- Takatsune Shimizu
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Walied A Kamel
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.,Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan.,Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Sayaka Yamaguchi-Iwai
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yumi Fukuchi
- Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Akihiro Muto
- Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
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22
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Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLoS One 2017; 12:e0176448. [PMID: 28459861 PMCID: PMC5411066 DOI: 10.1371/journal.pone.0176448] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/11/2017] [Indexed: 02/02/2023] Open
Abstract
Although geographic ecological studies and observational studies find that ultraviolet B exposure and 25-hydroxyvitamin D [25(OH)D] concentrations are inversely correlated with 15-20 types of cancer, few randomized controlled trials (RCTs) of vitamin D support those findings. The poor design of some RCTs may account for that lack of support. Most vitamin D RCTs to date have considered the vitamin D dose, rather than initial, final, or changes in, serum 25(OH)D concentrations. Here a model is developed for use in designing and analyzing vitamin D RCTs with application to cancer incidence. The input variables of the model are vitamin D dose, baseline and achieved 25(OH)D concentrations, known rates of cancer for the population, and numbers of participants for the treatment and placebo arms is estimated-vitamin D dosage and numbers of participants are varied to achieve desired hazard ratio significance, using information from two vitamin D RCTs on cancer incidence conducted in Nebraska with good agreement between the model estimates and reported hazard ratios. Further improvements to the conduct of vitamin D RCTs would be to start the trial with a moderate bolus dose to achieve the desired 25(OH)D concentrations, and bloodspot 25(OH)D assay use in summer and winter annually to monitor seasonal and long-term changes in 25(OH)D concentration and compliance, and to allow dosage adjustment for achievement of desired vitamin D status.
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Affiliation(s)
- William B. Grant
- Sunlight, Nutrition, and Health Research Center, San Francisco, California, United States of America
| | - Barbara J. Boucher
- Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
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23
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Costa PLF, França MM, Ferraz-de-Souza B. Nonspecific binding of a frequently used vitamin D receptor (VDR) antibody: important implications for vitamin D research in human health. Endocrine 2016; 54:556-559. [PMID: 27393303 DOI: 10.1007/s12020-016-1036-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/22/2016] [Indexed: 01/04/2023]
Affiliation(s)
- Pedro L F Costa
- Divisão de Endocrinologia e Laboratórios de Investigação Médica 18 e 25 (LIM-18 e LIM-25), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 01246-903, Brazil
| | - Monica M França
- Divisão de Endocrinologia e Laboratórios de Investigação Médica 18 e 25 (LIM-18 e LIM-25), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 01246-903, Brazil
| | - Bruno Ferraz-de-Souza
- Divisão de Endocrinologia e Laboratórios de Investigação Médica 18 e 25 (LIM-18 e LIM-25), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, 01246-903, Brazil.
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24
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Leung HW, Muo CH, Liu CF, Chan AL. Vitamin D3 Intake Dose and Common Cancer: A Population-Based Case Control Study in a Chinese Population. J Cancer 2016; 7:2028-2034. [PMID: 27877218 PMCID: PMC5118666 DOI: 10.7150/jca.16505] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/18/2016] [Indexed: 12/15/2022] Open
Abstract
Objectives: Epidemiological studies suggest that vitamin D status is associated inversely with risk of common cancers in western populations. This study aimed to investigate whether vitamin D is associated with risk of common cancers in Chinese population. Methods: A population-based retrospective case-control study was conducted analyzing data retrieved from the Catastrophic Illness Patient Databases (CIPD) and longitudinal health insurance database (LHID) from January 1, 2010 to December 31, 2011and January 1, 2000 to December 31, 2011, respectively. Cases were identified as subjects diagnosed with site-specific cancers (International Classification of Diseases, Ninth Revision,) and frequency matched to select controls. Use of vitamin D3 was compared between two groups. Odds ratios (ORs) were employed to quantify the risk associated with exposure to vitamin D3 by logistic regression. Results: There were 1.21% (1961/161806) patients in cases and 0.67 % (1092/161806) patients in controls identified were vitamin D3 users. Overall risk of cancers associated with vitamin D3 users was 1.67 (95% CI:1.55 -1.81). Among these, the risk of kidney cancer and bladder cancer associated with intakes of vitamin D3 were significant (OR 2.59; 95% CI 1.81-3.70; OR 4.97; 95% CI 4.40-5.60) in an adjusted model. In further stratification analysis, we found a statistically significant risk of bladder cancer associated with high intake of vitamin D3. Except this, no statistically significant risk of other site-specific cancers associated with high intake of vitamin D3. Conclusion: Except bladder cancer in stratification analysis, we observed no statistically significant association between high intake of vitamin D3 and other site-specific cancers.
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Affiliation(s)
- Henry Wc Leung
- Department of Radiation Therapy, An-Nan Hospital, China Medical University, Tainan, Taiwan;; Department of Nursing, Min-Hwei College of Health Care management, Tainan City 736, Taiwan
| | - Chih-Hsin Muo
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Chung-Feng Liu
- Department of Information Management, Chia Nan University of Pharmacy & Science, Tainan City 71710, Taiwan
| | - Agnes Lf Chan
- Department of Nursing, Min-Hwei College of Health Care management, Tainan City 736, Taiwan;; Department of Pharmacy, An-Nan Hospital, China Medical University, Tainan, Taiwan
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25
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Ferronato MJ, Alonso EN, Gandini NA, Fermento ME, Villegas ME, Quevedo MA, Arévalo J, López Romero A, Rivadulla ML, Gómez G, Fall Y, Facchinetti MM, Curino AC. The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression. J Steroid Biochem Mol Biol 2016; 163:193-205. [PMID: 27208626 DOI: 10.1016/j.jsbmb.2016.05.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 04/26/2016] [Accepted: 05/17/2016] [Indexed: 01/05/2023]
Abstract
Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.
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Affiliation(s)
- María Julia Ferronato
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - Eliana Noelia Alonso
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - Norberto Ariel Gandini
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - María Eugenia Fermento
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - María Emilia Villegas
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - Mario Alfredo Quevedo
- Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Facultad de Ciencias Químicas, Ciudad Universitaria, Universidad Nacional de Córdoba, 5000 Córdoba, Argentina
| | - Julián Arévalo
- Servicio de Patología del Hospital Interzonal General de Agudos Dr. José Penna, Av. Láinez 2401, 8000 Bahía Blanca, Argentina
| | | | - Marcos Lois Rivadulla
- Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain
| | - Generosa Gómez
- Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain
| | - Yagamare Fall
- Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain
| | - María Marta Facchinetti
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina
| | - Alejandro Carlos Curino
- Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
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26
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Marcinkowska E, Wallace GR, Brown G. The Use of 1α,25-Dihydroxyvitamin D₃ as an Anticancer Agent. Int J Mol Sci 2016; 17:E729. [PMID: 27187375 PMCID: PMC4881551 DOI: 10.3390/ijms17050729] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/22/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022] Open
Abstract
The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues.
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Affiliation(s)
- Ewa Marcinkowska
- Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland.
| | - Graham R Wallace
- Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
| | - Geoffrey Brown
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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Mazziotti G, Maffezzoni F, Giustina A. Vitamin D-binding protein: one more piece in the puzzle of acromegalic osteopathy? Endocrine 2016; 52:183-6. [PMID: 26899438 DOI: 10.1007/s12020-016-0890-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 02/02/2016] [Indexed: 12/21/2022]
Affiliation(s)
- G Mazziotti
- Endocrine and Metabolic Disease Unit, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
- Endocrine Unit, Department of Medicine, Carlo Poma Hospital, Mantua, Italy
| | - F Maffezzoni
- Endocrine and Metabolic Disease Unit, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - A Giustina
- Endocrine and Metabolic Disease Unit, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
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28
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Ben-Eltriki M, Deb S, Adomat H, Tomlinson Guns ES. Calcitriol and 20(S)-protopanaxadiol synergistically inhibit growth and induce apoptosis in human prostate cancer cells. J Steroid Biochem Mol Biol 2016; 158:207-219. [PMID: 26709138 DOI: 10.1016/j.jsbmb.2015.12.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 11/27/2015] [Accepted: 12/01/2015] [Indexed: 12/31/2022]
Abstract
The potential cancer preventive roles of calcitriol, the dihydroxylated metabolite of Vitamin D3, as well as 20(S)-protopanaxadiol (aPPD), the aglycone of the protopanaxadiol family of ginsenosides, have gained much attention in recent years for the prevention/treatment of prostate cancer (PCa). In the present study, we evaluated the anticancer and chemosensitization effects of calcitriol at clinically relevant concentrations and aPPD, either alone or in combination, in two well-characterized human PCa cell lines: androgen-sensitive non-metastatic LNCaP cells and androgen-independent metastatic C4-2 cells. The effects of the treatments on PCa cell viability and proliferation rates were evaluated by MTS and Brdu assays, respectively. Combination Indices (CI) and Dose Reduction Indices (DRI) were estimated to assess synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). Then, we determined the potential Pharmacodynamic interaction mechanisms as follows: The protein expression levels of the genes those are known to control cell cycle (cyclin D1 and cdk2); apoptosis (Bcl-2, Bax, and Capspases 3), androgen receptor and Vitamin D receptors were examined upon combinational treatment. The cell viability assay data show that addition of 10nM calcitriol to aPPD significantly lowered its IC50 values from the range of 41-53μM to 13-23μM, in LNCaP and C4-2 prostate cancer cells. The cell proliferation rate was significantly lower for combination treatments compared to the cells treated with aPPD alone. Similarly, Western blot results indicate that aPPD significantly upregulated Vitamin D receptor (VDR) expression, while calcitriol further enhanced the ability of aPPD to induce pro-apoptotic BAX, increased cleaved caspase-3 and downregulate cdk2 protein levels. Thus, the pharmacodynamic interaction between aPPD and calcitriol in impacting growth inhibition and apoptosis appears to be synergistic in nature. In conclusion, calcitriol sensitizes PCa cells to aPPD-mediated anticancer effects by enhancing its ability to induce apoptosis and reduce cell proliferation, and this synergism may limit calcitriol toxicity by facilitating the use of lower calcitriol doses. The associated increase in VDR expression and calcitriol half-life may be mechanistically associated with this sensitization effect.
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Affiliation(s)
- Mohamed Ben-Eltriki
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Experimental Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Subrata Deb
- Department of Biopharmaceutical Sciences, College of Pharmacy at Roosevelt University, Schaumburg, IL, USA
| | - Hans Adomat
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada
| | - Emma S Tomlinson Guns
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
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29
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Ben-Eltriki M, Deb S, Guns EST. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions. J Cancer 2016; 7:391-407. [PMID: 26918053 PMCID: PMC4749360 DOI: 10.7150/jca.13470] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 10/18/2015] [Indexed: 12/14/2022] Open
Abstract
Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy.
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Affiliation(s)
- Mohamed Ben-Eltriki
- 1. The Vancouver Prostate Centre at Vancouver General Hospital, Vancouver, BC, Canada
- 2. Department of Experimental Medicine, University of British Columbia, Vancouver, B.C, Canada
| | - Subrata Deb
- 4. Department of Biopharmaceutical Sciences, College of Pharmacy at Roosevelt University, Schaumburg, IL, USA
| | - Emma S. Tomlinson Guns
- 1. The Vancouver Prostate Centre at Vancouver General Hospital, Vancouver, BC, Canada
- 3. Department of Urologic Sciences, University of British Columbia, Vancouver, B.C, Canada
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30
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Sarno G, Daniele G, Tirabassi G, Chavez AO, Ojo OO, Orio F, Kahleova H, Balercia G, Grant WB, De Rosa P, Colao A, Muscogiuri G. The impact of vitamin D deficiency on patients undergoing kidney transplantation: focus on cardiovascular, metabolic, and endocrine outcomes. Endocrine 2015; 50:568-74. [PMID: 25999028 DOI: 10.1007/s12020-015-0632-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 05/13/2015] [Indexed: 02/06/2023]
Abstract
Vitamin D deficiency is common among kidney transplant (KT) recipients because of reduced sunlight exposure, low intake of vitamin D, the immunosuppressive drug regimen administered, and steroid therapy. Glucocorticoids regulate expression of genes coding for enzymes that catabolize vitamin D, further reducing its level in serum. Although vitamin D primarily regulates calcium homeostasis, vitamin D deficiency is associated with the risk of several diseases, such as diabetes mellitus and tuberculosis. Aim of this review is to highlight endocrine and metabolic alterations due to the vitamin D deficiency by evaluating the mechanisms involved in the development of KT-related disease (cardiovascular, bone mineral density, and new-onset diabetes after transplantation). Next, we review evidence to support a link between low vitamin D status and KT-related diseases. Finally, we briefly highlight strategies for restoring vitamin D status in KT patients.
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Affiliation(s)
- Gerardo Sarno
- Department of General Surgery and Transplantation Unit, San Giovanni di Dio e Ruggi D'Aragona University Hospital, Scuola Medica Salernitana, Salerno, Italy
| | - Giuseppe Daniele
- Divisions of Diabetes and Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Giacomo Tirabassi
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Alberto O Chavez
- Divisions of Diabetes and Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Opeolu O Ojo
- Faculty of Life and Health Sciences, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK
| | - Francesco Orio
- Sports Science and Wellness, University Parthenope Naples, Naples, Italy
- Endocrinology and Diabetology, San Giovanni di Dio e Ruggi D'Aragona University Hospital, Scuola Medica Salernitana, Salerno, Italy
| | - Hana Kahleova
- Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Giancarlo Balercia
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona, Italy
| | - William B Grant
- Sunlight, Nutrition, and Health Research Center, San Francisco, CA, USA
| | - Paride De Rosa
- Department of General Surgery and Transplantation Unit, San Giovanni di Dio e Ruggi D'Aragona University Hospital, Scuola Medica Salernitana, Salerno, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Federico II University Hospital, Federico II University, Naples, Italy
| | - Giovanna Muscogiuri
- Department of Clinical Medicine and Surgery, Federico II University Hospital, Federico II University, Naples, Italy.
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31
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Zhang ZZ, Li Y, Wang M, Xu F. Significance of β-catenin and vitamin D receptor expression in colorectal carcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:3700-3705. [DOI: 10.11569/wcjd.v23.i23.3700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of β-catenin and vitamin D receptor (VDR) in colorectal carcinoma to explore their roles in colorectal carcinoma pathogenesis.
METHODS: The expression of β-catenin and VDR was detected by immunohistochemistry in 65 colorectal carcinoma specimens and 65 normal colorectal mucosa specimens.
RESULTS: The missing expression of β-catenin on the cell membrane and ectopic expression in colorectal carcinoma specimens and normal colorectal mucosa specimens had a significant difference (P < 0.01). The strongly positive expression of VDR in colorectal carcinoma specimens and normal colorectal mucosa specimens had a significant difference (P < 0.01). The abnormal expression of β-catenin was positively correlated with that of VDR in colorectal carcinoma (r = 0.98, P < 0.01), and both were found to be associated with lymph node metastasis and tumor invasion.
CONCLUSION: Lower expression of VDR may influence β-catenin and activate the Wnt signaling pathway in human colorectal carcinoma. Detecting the abnormal expression of β-catenin and VDR may be helpful for the diagnosis and evaluation of the prognosis of colorectal carcinoma.
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32
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Schmutz EA, Zimmermann MB, Rohrmann S. The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements. Eur J Nutr 2015; 55:393-402. [PMID: 25701092 DOI: 10.1007/s00394-015-0860-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 02/09/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements. METHODS We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were estimated by proportional hazards regression. RESULTS Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95% CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 μg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant. CONCLUSIONS 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.
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Affiliation(s)
- Einat Avital Schmutz
- Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Michael Bruce Zimmermann
- Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Sabine Rohrmann
- Department of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland.
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Pilon C, Rebellato A, Urbanet R, Guzzardo V, Cappellesso R, Sasano H, Fassina A, Fallo F. Methylation Status of Vitamin D Receptor Gene Promoter in Benign and Malignant Adrenal Tumors. Int J Endocrinol 2015; 2015:375349. [PMID: 26843863 PMCID: PMC4710947 DOI: 10.1155/2015/375349] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/10/2015] [Indexed: 01/04/2023] Open
Abstract
We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5' regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesis.
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Affiliation(s)
- Catia Pilon
- Clinica Medica 3, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Andrea Rebellato
- Clinica Medica 3, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Riccardo Urbanet
- Clinica Medica 3, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Vincenza Guzzardo
- Cytopathology Unit, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Rocco Cappellesso
- Cytopathology Unit, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Ambrogio Fassina
- Cytopathology Unit, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
| | - Francesco Fallo
- Clinica Medica 3, Department of Medicine-DIMED, University of Padova, 35128 Padova, Italy
- *Francesco Fallo:
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Irving AA, Yoshimi K, Hart ML, Parker T, Clipson L, Ford MR, Kuramoto T, Dove WF, Amos-Landgraf JM. The utility of Apc-mutant rats in modeling human colon cancer. Dis Model Mech 2014; 7:1215-25. [PMID: 25288683 PMCID: PMC4213726 DOI: 10.1242/dmm.016980] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.
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Affiliation(s)
- Amy A Irving
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Kazuto Yoshimi
- Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Marcia L Hart
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
| | - Taybor Parker
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA
| | - Linda Clipson
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Madeline R Ford
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Takashi Kuramoto
- Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - William F Dove
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - James M Amos-Landgraf
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA. Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
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Aragón F, Perdigón G, LeBlanc ADMD. Modification in the diet can induce beneficial effects against breast cancer. World J Clin Oncol 2014; 5:455-464. [PMID: 25114859 PMCID: PMC4127615 DOI: 10.5306/wjco.v5.i3.455] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The population tends to consume foods that in addition to their nutritional values can offer some benefits to their health. There are many epidemiological evidences and research studies in animal models suggesting that diet plays an important role in breast cancer prevention or progression. This review summarized some of the relevant researches about nutrition and cancer during the last years, especially in breast cancer. The analysis of probiotics and fermented products containing lactic acid bacteria in cancer prevention and/or treatment was especially discussed. It was observed that a balance of fatty acids similar to those of traditional Mediterranean diet, the consumption of fruits and vegetables, dietary fiber intake, vitamin supplementation are, along with the intake of probiotic products, the most extensively studied by the negative association to breast cancer risk. The consumption of probiotics and fermented products containing lactic acid bacteria was associated to reduce breast cancer risk in some epidemiological studies. The use of animal models showed the modulation of the host’s immune response as one of the important effects associated to the benefices observed with most probiotics. However; future assays in human are very important before the medical community can accept the addition of probiotic or fermented milks containing lactic acid bacteria as supplements for cancer patients.
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Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, Gluud C. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev 2014; 2014:CD007469. [PMID: 24953955 PMCID: PMC11285304 DOI: 10.1002/14651858.cd007469.pub2] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory. OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded, and the Conference Proceedings Citation Index-Science to February 2014. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults who were healthy or were recruited among the general population, or diagnosed with a specific disease. Vitamin D could have been administered as supplemental vitamin D (vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS Two review authors extracted data independently. We conducted random-effects and fixed-effect model meta-analyses. For dichotomous outcomes, we calculated the risk ratios (RRs). We considered risk of bias in order to assess the risk of systematic errors. We conducted trial sequential analyses to assess the risk of random errors. MAIN RESULTS Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D₃, one trial tested vitamin D₂, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I² = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for-profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I² = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D₃ versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I² = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D₃ trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D₃ decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I² = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D₃ combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I² = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review. AUTHORS' CONCLUSIONS There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D₃ supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D₃ and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D₃, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias.
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Affiliation(s)
- Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Kate Whitfield
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812CopenhagenDenmark
| | - Goran Krstic
- Environmental Health ServicesFraser Health Authority#218 ‐ 610 Sixth StreetNew WestminsterBCCanadaV3L 3C2
| | - Jørn Wetterslev
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812CopenhagenDenmark
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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