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Research Identifies A New Mechanism For Selenium In Repressing Prostate Cancer (June 2004)
Many avenues of research are providing experimental
evidence supporting the concept that selenium plays an important role in
inhibiting the development and progression of prostate cancer. It has
been clearly established that selenium participates in the detoxifying
enzymes that protect the prostate from damage resulting from oxidative
stress. The new research identifies a second function. Selenium directly
binds and inhibits an important enzyme, 5-Lipoxygenase (5-LOX), that
facilitates one of the three major pathways that recruits arachidonic
acid from the cell wall and sequentially processes it into an important
class of metabolic regulators, the leukotrienes. The currently available
Cox-2 inhibitors interrupt a closely associated enzyme system (cyclooxygenase)
in another of the arachidonate metabolic pathways, a pathway whose end
products are the prostaglandins, thromboxanes, and prostacyclins. But
unlike "prostaglandin", the mention of which usually elicits a knowing
nod, "the leukotrines" have escaped common recognition. However,
emerging research is assigning it an important role in carcinogenesis,
to date mostly associated with pancreatic and esophageal cancer. The new
findings demonstrate that selenium-caused inhibition of 5-LOX results in
an arrest of prostate cell growth and proliferation, and leads to rapid
apoptosis in prostate cancer cells. The research was reported by J.
Ghosh, Department of Urology, Vattikuti Urology Institute, Henry Ford
Health System, Detroit, in the article, "Rapid induction of apoptosis in
prostate cancer cells by selenium: [and its] reversal by metabolites of
arachidonate 5-lipoxygenase" (Biochemical and Biophysical Research
Communications 315, 2004: 624-635).
The analysis sets out to address "the underlying molecular
mechanisms by which selenium exerts it anti-cancer effect" and commences
by noting "multiple reports supporting a role for arachidonic acid, a
common fatty acid in Western-style diets (red meat, egg yolks, and dairy
products) in the proliferation of prostate cancer cells". Cellular
growth stimuli, such as from epidermal growth factor, promote the
release of this primary building block from the cell membrane into the
synthesis pathway for the important metabolic regulators. The metabolic
pathway of interest in this study requires the enzyme,
5-lipoxygenase (5-LOX); and the research found selenium binds and
inactivates LOX-5 and thereby "triggers massive apoptosis of prostate
cancer cells". However, the addition of exogenous arachidonic acid to
the in vitro test (analogous to what might result from the
typical Western diet), substantially prevents this apoptosis. Of
importance was the observation that in these studies in which selenium
blocked the 5-LOX enzyme, normal prostate cells were not
affected, whereas the growth of prostate cancer cells was
markedly inhibited. This suggested a difference in sensitivity to the
selenium interference of LOX-5. If metabolic products further
"downstream" to the blocked enzyme were added to the tests in which the
5-LOX was selenium-blocked, the apoptosis of prostate cancer cells did
not occur. "Pretreatment of cells with arachidonic acid significantly
reduced selenium-induced apoptosis in prostate cancer cells in a dose
dependent manner." Specific pharmacological inhibitors of 5-LOX are
available that can cooperate with selenium in inhibiting growth of
prostate cancer cells and Ghosh's research substantiated synergism
between selenium and these additional inhibitors, leading to the
speculation "that an optimized combination of selenium and 5-LOX
inhibitors might be more effective than selenium alone in controlling
prostate cancer."
What are the broad implications that can be inferred from
this research? Ghosh states one: "our research suggests diets rich in
arachidonic acid and its precursor fatty acids [such as is found in the
typical Western type diet, rich in linoleic acid, an omega 6 fatty
acid], may interfere with the anti-cancer effects of selenium". Since
these fatty acids, found abundantly in Western diets, can stimulate
growth and inhibit apoptosis in human prostate cancer cells in vitro,
then a diet rich in arachidonic acid and its precursors may promote the
development and progression of prostate cancer. By extension from the
research findings, it is possible that the hoped for beneficial effect
from the supplemental 200 mcg of selenium used in prostate cancer
prevention (and in one arm of the SELECT trial) could be lessened by
high dietary fat intake. This implication, of course, extends also to a
possible decrease in the basic protection afforded by the naturally
occurring dietary selenium intake of 70 to 120 mcgs daily in the United
States.
Bottom Line: A diet rich in red meat, cheese, whole milk, and egg
yolks may lessen selenium's potential protection against the development
and progression of prostate cancer.
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