Page 76 - Vitamin D and Cancer

3 Anti-inflammatory Activity of Calcitriol in Cancer 63

3.4 The Role of Anti-inflammatory Effects of Calcitriol
in Cancer Prevention and Treatment

As already discussed, current perspectives in cancer biology suggest that
inflammation plays a role in the development of cancer [67, 126, 127]. De Marzo
et al. [128] have proposed that the PIA lesions in the prostate, which are associated
with acute or chronic inflammation, are precursors of prostatic intraepithelial neo-
plasia (PIN) and PCa. The epithelial cells in PIA lesions have been shown to exhibit
many molecular signs of stress including elevated expression of COX-2 [51, 126].
Inflammatory bowel disease is associated with the development of CRC [129–131].
Based on the recent research demonstrating anti-inflammatory effects of calcitriol
(as discussed in the preceding sections) in the malignant cells as well as the infil-
trating cells at the tumor sites, we postulate that calcitriol may play a role in delay-
ing or preventing cancer development and/or progression.

3.4.1 Calcitriol and Prostate Cancer Chemoprevention

PCa generally progresses very slowly, likely for decades, before symptoms
become obvious and diagnosis is made [132]. Recently, inflammation in the
prostate has been proposed to be an etiological factor in the development of PCa [67].
The observed latency in PCa provides a long window of opportunity for inter-
vention by chemopreventive agents. Dietary supplementation of COX-2 selec-
tive NSAIDs such as celecoxib has been shown to suppress prostate carcinogenesis
in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model [133].
Our studies on the inhibitory effects of calcitriol on COX-2 expression and the
PG pathway and MKP5 induction with the resultant stress kinase inactivation
and inhibition of pro-inflammatory cytokine production as well as published
observations of calcitriol actions to inhibit NFkB signaling suggest that calcit-
riol exhibits significant anti-inflammatory effects in vitro. Therefore, we
hypothesize that calcitriol has the potential to be useful as a chemopreventive
agent in PCa. Recently, Foster and coworkers have demonstrated that adminis-
tration of high dose calcitriol (20 mg/kg), intermittently 3 days/week for up to
14–30 weeks, suppresses prostate tumor development in TRAMP mice [134, 135].
The efficacy of calcitriol as a chemopreventive agent has also been examined in
Nkx3.1; Pten mutant mice, which recapitulate stages of prostate carcinogenesis
from PIN lesions to adenocarcinoma [136]. The data reveal that calcitriol
significantly reduces the progression of PIN from a lower to a higher grade.
Calcitriol is more effective when administered before, rather than subsequent to,
the initial occurrence of PIN. These animal studies as well as our in vitro
observations suggest that clinical trials in PCa patients with PIN or early disease
evaluating calcitriol and its analogs as agents that prevent and/or delay
progression, are warranted.