The body needs plain vitamin D3 to support its mechanisms for waging war against prostate cancer, according to a groundbreaking study presented Mar 31 to the American Association for Cancer Research at its annual meeting.(1)
The new research - conducted by investigators at the University of Toronto and University of Illinois - “points to the mechanisms by which vitamin D affects the rate of prostate cancer growth” and “indicates that vitamin D may slow the growth of prostate cancer cells.” That is:
1. Oral doses of plain vitamin D raise levels of calcitriol (a hormone made from vitamin D) in prostate tissue.
2. Higher prostate levels of calcitriol both correspond with lower levels of the proliferation marker Ki67…
3. And increase levels of cancer growth-inhibitory microRNAs in prostate cancer cells.
These are crucial findings, given that until now the role of vitamin D in prostate cancer has been “controversial, with some suggesting that higher levels of vitamin D should be avoided,” says lead investigator Reinhold Vieth, PhD, at the University of Toronto.
According to Dr. Vieth:
• “This study shows calcitriol makes the foot come off the gas pedal of cancer growth.
• “We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign.
• “We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer.”
Dr. Vieth and colleagues previously reported that higher vitamin D levels were slowing the rate of rise in prostate-specific antigen levels among men who were being monitored regularly for prostate cancer.
In the current double blind clinical trial, they randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in three different doses of 400, 10,000, or 40,000 IU for three to eight weeks before surgery.
And they found that:
• Calcitriol levels in the prostate increased progressively with each daily dose of vitamin D,
• With 40,000 IU showing the highest levels.
• These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth,
• As well as higher levels of specific growth-inhibitory microRNAs.
Dr. Vieth and his colleagues stress that they do not advocate vitamin D supplementation in doses higher than 4,000 IU daily.
They assigned one group of patients in this study to the 40,000 IU daily dose owing to the short presurgical time frame available for study, not as a regular regimen.
“Plain vitamin D provides the raw material to permit the body to take care of its own needs,” says Dr. Vieth.
“We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes.”
Next Step a Phase III Placebo-Controlled Study
The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a “high” dose of plain vitamin D.
This research was funded by the Canadian Cancer Society and was a collaboration between investigators at University Health Network, Sunnybrook Hospital, and Mount Sinai Hospital, all in Toronto, and at the University of Chicago.
Source: Based on American Association for Cancer Research news release, Mar 31, 2012
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1. Presentation Abstract:
"Double-blind randomized clinical trial of vitamin D3 showing effects on tissue calcitriol levels, gene expression, and proliferation immunochemistry in prostate cancer"
- From AACR Annual Meeting 2012 (abstract # LB-435)
By Dennis Wagner, Reinhold Vieth, et al.*
Background: Preclinical data suggest that vitamin D plays a favourable role in prostate cancer prevention and prognosis, but its putative anticancer effects have not been validated in clinical prostate tissue samples. Here, we report the results from a randomized clinical trial (RCT).
Objectives: We conducted an RCT to determine whether simple cholecalciferol (vitamin D3) consumed orally elicits effects on prostate cancer pathology in prostate tissue obtained at surgery.
Methods: Prostate cancer patients (n=66) with Gleason scores 6 or 7 and scheduled for radical prostatectomy were randomized to daily vitamin D doses of 400, 10,000, or 40,000 IU for 3-8 wk before surgery.
Results: Laser-capture microdissected paraffin-embedded prostate tissue showed differential expression, between benign and cancerous regions, for the cancer-related mRNAs and miRNAs, as well as for the Ki-67 proliferation marker (p0.07 among groups).
The group consuming 40,000 IU/d vitamin D exhibited the highest levels of both calcitriol and its precursor as measured in frozen prostate tissue and in serum (p<0.02 each).
Prostate tissue calcitriol correlated strongly with the expression of androgen receptor mRNA (r = -0.58, p=0.001), NKX3.1 mRNA (r = -0.39, p=0.02), miR-100 (r = 0.44, p=0.01), miR-125b (r = 0.37, p=0.03), Let-7a (r = 0.47, p=0.03), miR-141 (r = 0.51, p=0.002), miR-106b (r = 0.45, p=0.01), and miR-331-3p (r = 0.47, p=0.005).
Automated digital analysis of immunohistochemically stained prostate cancer regions showed that prostate tissue calcitriol related negatively with Ki67 intensity (r = -0.38, p =0.02) and percent of nuclei stained strongly positive (3+) for Ki67 (r = -0.41, p=0.008).
A threshold effect was evident such that patients at the highest quartile of prostate tissue calcitriol (? 37 pmol/kg) had significantly lower AR mRNA (p<0.001), NKX3.1 mRNA (p=0.01), and Ki67 measures (p<0.05), as well as higher levels of the correlated miRNAs (p<0.05), compared to those with lower levels.
Conclusions: We provide level-1 clinical evidence:
• That higher oral vitamin D doses produce higher levels of calcitriol within prostate tissue,
• And that higher prostate calcitriol relates to lower androgen receptor mRNA, higher miRNA signalling, and diminished expression of the proliferation marker Ki67 in prostate cancer.
These RCT results justify a need to explore strategies that may maximize calcitriol within prostate for cancer chemoprevention.
* Dennis Wagner, Larisa Nonn, Angeline Antonio, Avani Vaishnav, Laurence Klotz, Neil Fleshner, Antonio Finelli, Dominique Trudel, Theodorus Van der Kwast, Reinhold Vieth. University of Toronto/Mount Sinai Hospital, Toronto, ON, Canada; University of Illinois at Chicago, Chicago, IL; Sunnybrook Health Sciences Centre, Toronto, ON, Canada; University Health Network, Toronto, ON, Canada.