Low doses of the active
form of vitamin D and non-steroidal anti-inflammatory drugs (NSAIDs),
taken in combination, have been shown to act as a powerful one-two punch
that
knocks down the growth of prostate cancer cells.
In a study published in the journal Cancer
Research, scientists from
Stanford University discovered that the amount of both -- activated vitamin
D, or calcitriol, and the NSAIDs -- could be reduced by half to one-tenth
the dosage to thwart prostate cancer cell growth in cell lines and primary
tissue cultures.
If work in animal models and human trials confirm the findings, the
drug combination may help to keep the NSAID family of drugs among the
pharmaceutical choices for the prevention and treatment of cancer. This
list includes ibuprofen, indomethacin and naproxen, in addition to other
so-called COX-2 inhibitors linked to increased risk for cardiovascular
disease, including Vioxx® and Celebrex®.
“ NSAIDs have their own risks,” said David Feldman,
M.D., professor of Medicine in the Division of Endocrinology, Gerontology
and
Metabolism at the Stanford University School of Medicine.
“ So,
we have to be careful even with lower doses and we still need to watch
the patients very closely if we intend to keep them on these drugs for
extended periods of time. But we are aiming to find doses that are less
toxic and far more tolerable for the patient.”
As outlined in their study, the Stanford scientists discovered that
vitamin D, known as the “sunshine vitamin,” works to limit
the growth of prostate cancer cells by interfering with the same molecules
attacked by NSAIDs -- the prostaglandin/COX-2 pathway.
Prostaglandins are responsible for activating the inflammatory response
that results in pain and fever. NSAIDs work by blocking an enzyme called
cyclooxygenase-2 or COX-2 which is essential for prostaglandin synthesis,
thereby relieving some of the effects of pain and fever.
In this study, activated vitamin D or calcitriol was shown to act as
a triple threat against this pathway, in prostate cancer cells:
- First, it limits the expression of a key enzyme needed to synthesize
prostaglandins into
COX-2.
- Second, it increases the expression of an enzyme that rapidly disassembles
active prostaglandin molecules, thus promoting the breakdown of the
hormone.
- Third, the scientists discovered that calcitriol inhibits the production
of two cell receptors used by prostaglandins to regulate gene expression
and control tumor proliferation.
While the scientists showed that activated vitamin D, calcitriol,
works by itself to limit prostate cancer growth, it is equally
effective in
much smaller doses when used in combination with NSAIDs. Furthermore,
calcitriol dramatically reduces the amount of NSAIDs necessary
to curb prostate cancer cell growth.
This is particularly important now, in light of recent studies showing
that some NSAIDs that are selective for COX-2 targeting, such as rofecoxib
(Vioxx®) and celecoxib (Celebrex®), are linked to cardiovascular
disease at their prescribed doses.
While their studies provide insight into cellular activities controlled
by both calcitriol and the NSAIDs, Feldman and his colleagues remain
cautious about advancing their new-found understanding of prostaglandin
chemistry into patients.
“We need to verify that vitamin D and NSAIDs work in synergy
not just in these cell lines, but also work in the same manner, in
humans
which have a vastly more complex physiology than simple cells in a culture
plate,” Feldman said.
Vitamin D is converted in the liver and kidney to the active form called
calcitriol, a hormone that has widespread actions in the body. The Feldman
laboratory used calcitriol in the experiments reported in the Cancer
Research article. Vitamin D in the form available over the counter is
useful for protection of bones, but would not achieve the therapeutic
levels of calcitriol needed to inhibit cancer cell growth, since the
body has mechanisms to limit its activation to calcitriol, Feldman explained.
Other Stanford scientists contributing to this study included Jacqueline
Moreno, Ph.D., the lead author; Aruna Krishnan, Ph.D.; Srilatha Swami,
Ph.D.; Larisa Nonn, Ph.D.; and Donna M. Peehl, Ph.D. The work was supported
by grants from the National Institutes of Health and the Department of
Defense.
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was first published by the American Association for Cancer Research
on 1st September 2005. For further information, please visit their
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