Page 77 - Vitamin D and Cancer

64 A.V. Krishnan and D. Feldman

3.5 Summary and Conclusions

Our recent research has identified several new calcitriol target genes revealing
novel molecular pathways of calcitriol action in prostate cells. The data suggest that
calcitriol has anti-inflammatory actions that contribute to its therapeutic and can-
cer-preventive effects in PCa. Calcitriol reduces both PG production (by suppress-
ing COX-2 and increasing 15-PGDH expression) and PG biological actions (by PG
receptor down-regulation). We propose that calcitriol inhibition of the PG pathway
contributes significantly to its anti-inflammatory actions. Combinations of calcit-
riol with NSAIDs exhibit synergistic enhancement of growth inhibition in PCa cell
cultures, suggesting that they may have therapeutic utility in PCa. The results of our
recent clinical trial in patients with early recurrent PCa indicate that the combina-
tion of a weekly high dose calcitriol with the nonselective NSAID naproxen has
activity to slow the rate of rise of PSA in most patients. Another novel molecular
pathway of calcitriol action in prostate cells involves the induction of MKP5
expression and the subsequent inhibition of p38 stress kinase signaling, resulting in
the attenuation of the production of pro-inflammatory cytokines. There is also con-
siderable evidence for an anti-inflammatory role for calcitriol in several cancers
through the inhibition of NFkB signaling in many cancer cells as well as the infil-
trating cells present at the tumor sites. The discovery of these novel calcitriol-
regulated pathways suggest that calcitriol has anti-inflammatory actions, which in
addition to its other anticancer effects, may play an important role in the prevention
and/or treatment of cancer. We conclude that calcitriol may have utility as a cancer
chemopreventive agent. Calcitriol and its analogs may also have therapeutic utility,
particularly in PCa and should therefore be evaluated in clinical trials in PCa
patients with early or precancerous disease.

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