Page 66 - Vitamin D and Cancer

Chapter 3
Anti-inflammatory Activity of Calcitriol
in Cancer

Aruna V. Krishnan and David Feldman

Abstract Calcitriol exerts antiproliferative and pro-differentiating actions in many
malignant cells and in animal models of cancer and its use as an anticancer agent
in patients is currently being evaluated. Several molecular pathways are involved in
the growth inhibitory effects of calcitriol, resulting in cell cycle arrest, induction of
apoptosis, and the inhibition of invasion, metastasis, and angiogenesis. This chap-
ter describes recent research revealing that anti-inflammatory effects are an addi-
tional anticancer pathway of calcitriol action and some of the molecular pathways
underlying these effects are discussed. In normal and malignant prostate epithelial
cells, calcitriol inhibits the synthesis and biological actions of pro-inflammatory
prostaglandins (PGs) by three actions: (1) the inhibition of the expression of
cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs; (2) the upregula-
tion of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme
that inactivates PGs; and (3) decreasing the expression of EP and FP PG receptors
that are essential for PG signaling. The combination of calcitriol and non-steroidal
anti-inflammatory drugs (NSAIDs) results in a synergistic inhibition of the growth
of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa.
Calcitriol also increases the expression of mitogen-activated protein kinase phos-
phatase 5 (MKP5) in prostate cells resulting in the subsequent inhibition of p38
stress kinase signaling and the attenuation of the production of pro-inflammatory
cytokines. There is also considerable evidence for an anti-inflammatory role for
calcitriol through the inhibition of nuclear factor kappa B (NFkB) signaling in
several cancer cells. The discovery of these novel calcitriol-regulated molecular
pathways reveals that calcitriol has anti-inflammatory actions, which in addition
to its other anticancer effects may play an important role in cancer prevention and
treatment.

D. Feldman (*)
Department of Medicine, Division of Endocrinology,
Stanford University School of Medicine,
300 Pasteur Drive, Stanford, CA 94305–5103, USA
e-mail: dfeldman@stanford.edu

D.L. Trump and C.S. Johnson (eds.), Vitamin D and Cancer, 53
DOI 10.1007/978-1-4419-7188-3_3, © Springer Science+Business Media, LLC 2011