Randomized Clinical Trial of Vitamin D3 Doses on Prostatic Vitamin D Metabolite Levels and Ki67 Labeling in Prostate Cancer Patients

Wagner, David G.; Trudel, Dominique; Kwast, Theodorus H. van der; Nonn, Larisa; Giangreco, Angeline A.; Li, Doris; Dias, Adriano Basso; Cardoza, Monique; Laszlo, Sanda; Hersey, Karen; Klotz, Laurence; Finelli, Antonio; Fleshner, Neil; Vieth, Reinhold

doi:10.1210/jc.2012-4019

Cited by 85 publications

(109 citation statements)

References 39 publications

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“…[14] In a study of prostate cancer patients (Gleason 6 or 7), oral vitamin D3 (400, 10,000 or 40,000 IU/d) administered before prostatectomy, raised prostate calcitriol levels and lowered PSA. [12] In a study of early stage low risk prostate cancer patients given vitamin D3 4000 IU/d for one year, a decrease in the number of positive cores at repeat biopsy was observed in more than half of the participants without a change in PSA. [15]…”

Section: Discussionmentioning

confidence: 99%

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Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial

Chandler

Giovannucci

Scott

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Black men exhibit a high prevalence of vitamin D deficiency as well as higher incidence of prostate cancer and higher mortality rates from prostate cancer than Whites. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on prostate specific antigen (PSA) in healthy Black men. Methods During 3 winters from 2007–2010, 105 Black men (median age, 48.9 years) of Boston, MA were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 IU of vitamin D3. At baseline and 3 months, free and total PSA were measured. Results With vitamin D supplementation, no significant differences in free and total PSA were observed; free PSA: −0.0004 ng/mL (p=0.94) and total PSA: −0.004 ng/mL (p=0.92) for each additional 1000 IU/d of vitamin D3. Conclusion Within an unselected population of healthy Black men without a cancer diagnosis, we found no effect of vitamin D supplementation on free or total PSA. Impact These findings support prior findings of no change in PSA with vitamin D supplementation and emphasize the need for new methods to assess the influence of vitamin D supplementation on prostate cancer prevention.

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Section: Discussionmentioning

confidence: 99%

“…days or weeks). [12] To our knowledge, this is the first study to examine the preventive benefits of vitamin D intake on PSA levels among men without a cancer diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial

Chandler

Giovannucci

Scott

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…LCM was used to separately collect benign epithelium, PCa epithelium and benign stroma via a procedure previously described for these samples [25]. Serum samples were obtained at entry and at the final visit before the previously described [26]. …”

Section: Methodsmentioning

confidence: 99%

Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model

Giangreco

Dambal

Wagner

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal–epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-α, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro-inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, which appears to be primarily produced by the prostatic epithelium. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma–epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland.

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“…Furthermore, in humans, OHD treatment can reduce ki67 staining (i.e. proliferation) in prostate tumours (Wagner et al 2013). In a phase 1 clinical trial, VDR agonist combined with docetaxel reduced PSA levels in patients with metastatic disease (Medioni et al 2014).…”

Section: Vitamin D Receptor (Vdr or Nr1i1)mentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

Leach

Powell

Bevan

2016

Endocrine-Related Cancer

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Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease -hence the quest for new effective therapies for 'castrate-resistant' prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC. The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear receptors in prostate cancer -a rapidly evolving field of research.

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Randomized Clinical Trial of Vitamin D3 Doses on Prostatic Vitamin D Metabolite Levels and Ki67 Labeling in Prostate Cancer Patients

Cited by 85 publications

References 39 publications

Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial

Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial

Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

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