Increasing evidence suggests that oral vitamin D3 supplements may reduce prostate inflammation, helping slow or even reverse progression of low-grade, less-aggressive prostate cancer without side effects, according to a summary of research presented at the American Chemical Society's National Meeting and Exposition.
Bruce Hollis, PhD, Professor of Pediatrics at Medical University of South Carolina, described early results of an ongoing randomized, controlled clinical trial in 37 men who had opted for elective prostatectomies and received 4,000 units of vitamin D3 per day or a placebo. After 60 days the prostate glands were removed and examined.
Preliminary results indicated that many of the men given the vitamin had improvements in their cancer, while tumors in the placebo group either stayed the same or worsened. Although additional research is necessary, Hollis said, it was clear that vitamin D caused dramatic changes in the expression levels of many cell lipids and proteins, particularly those involved in inflammation.
“Cancer is associated with inflammation, especially in the prostate gland. We don't know yet whether vitamin D treats or prevents prostate cancer. At the minimum, what it may do is keep lower-grade prostate cancers from going ballistic,” he told the meeting.
In a study published in 2012, he and colleagues at the Veterans Administration studied the response of 48 men with low-grade prostate cancer to vitamin D3 over one year (J Clin Endocrinol Metab 2012;97:2315-2324). Of 44 patients who completed the trial, 55 percent had a decrease in the number of positive cores or the Gleason score, 11 percent had no change, and 15 percent had an increase. Moreover, no adverse events were reported.
Now underway, Hollis noted, is a randomized controlled clinical trial by the VA on possible benefits in patients with prostate cancer or multiple sclerosis, with preliminary results expected within a year.
Mechanisms of Action
Hollis explained that vitamin D is metabolized and activated, and acts through receptors in a variety of human tissues affected by different cancers. Basic research has indicated that vitamin D provides certain cancer-fighting effects in addition to reducing inflammation, including pro-differentiation and anti-proliferation of tumor cells. Moreover, epidemiological studies have indicated that low circulating 25(OH)D levels are a risk factor in several cancers.
Nomadic tribes living near the equator, such as the Maasai in Kenya and Tanzania, have substantially lower higher levels of vitamin D, while African-Americans have lower levels and higher rates of prostate cancer—most likely due to high melanin in the skin, which reduces absorption of the vitamin from sunlight.
The protein most strongly induced by vitamin D is growth differentiation factor 15 (GDF15), he noted. Previous studies by other groups showed that GDF15 dials down inflammation, and many aggressive prostate cancers make little or no GDF15.
Dose Below that of Daily Sun Exposure
The vitamin D dose in the study is well below the amount received from daily sun exposure, Hollis noted, and there were no adverse events or significant changes in PSA levels.
“If this was a drug, it would be in the news every day. In our 2012 study we found a pretty astounding decrease in Gleason scores with 4,000 daily units,” he said, adding that the current recommended daily allowance of vitamin D and concern about kidney stones with higher levels was based on a 2011 Institute of Medicine review, primarily in 36,282 postmenopausal women aged 50 to 79 who participated in the Women's Health Initiative and were randomized into one of two study groups who took either 1,000 mg of calcium carbonate or 400 International Units of vitamin D.
“We do not see kidney stones from vitamin D supplements in our study.”
He said he would recommend 6,000 to 8,000 units of supplementary vitamin D for most adults as a preventive measure to reduce inflammation: “I am not saying taking it as an adjunct medication but to help reduce inflammation in low-grade prostate cancer instead of taking the knife to everyone.”
GDF-15 Gene Involvement
James Lambert, PhD, Associate Research Professor at the University of Colorado Cancer Center Anschutz Medical Campus, studies the inflammatory role of growth differentiation factor-15 (GDF-15) in prostate cancer.
In a study published in February in the journal Prostate (2015;75:255-253), he and his colleagues examined the relationship between the gene GDF-15 and prostate inflammation in prostate cancer specimens. GDF-15, which is upregulated by vitamin D, was decreased in prostate cancer samples with greater levels of inflammation.
Specifically, the researchers found that decreased GDF-15 expression in epithelial cells was associated with increased inflammation severity and an inverse relationship between it and CD3+, CD4+, CD8+, CD68+, and inos+ leukocytes as well as suppressed NFκB activity in luciferase reporter assays. They also discovered that expression of the NFκB target, interleukin 8 (IL-8), was downregulated by GDF-15.
“The inverse relationship between GDF-15 and inflammation demonstrates a novel expression pattern for GDF-15 in the human prostate, and suppression of NFκB activity may shed light on a potential mechanism for this inverse correlation,” they reported.
“Vitamin D inhibits prostate cancer growth, but there is not enough evidence yet that it is an anti-cancer agent,” Lambert cautioned. “Inflammation is thought to drive many cancers including prostate, gastric, and colon. Therefore, GDF-15 may help keep prostate tissue healthy by suppressing inflammation.”
The team found that GDF-15 suppresses inflammation by inhibiting NFκB, another molecular target, which has been studied extensively and shown to both promote inflammation and the formation and growth of tumors.
“Starting with vitamin D in prostate cancer we have come a long way toward understanding how we might use GDF-15 to target NFkB, which may have implications in cancer types far beyond prostate,” he said. “Vitamin D is a hormone, but little is known about the specific molecular mechanisms involved in vitamin D signaling, cancer inflammation, and tumor growth although we do know that inflammation can be a prostate cancer promoter.”
In early research he and his team thought that high GDF-15 levels would be found in normal prostate tissue and low levels associated with cancer, but this turned out not to be the case.
“However when we looked at prostatectomy samples, we discovered a significant correlation between GDF-15 protein and surrounding atrophic lesion. That led us to the hypothesis that the GDF-15 gene might somehow inhibit inflammation.”
He said that in the initial 2012 study Hollis et al found inflammatory markers and linked them to lower levels of vitamin D, but that it was only over one year and in small number of patients. “Three years later this is pretty interesting. If you take it at face value it is pretty impressive.”
Still, he stressed that vitamin D can have toxic effects at higher doses because it controls calcium homeostasis, and patients can become hypercalcemic, so recommending significantly increased intake of supplements needs to be carefully considered.Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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