Anti-inflammatory Activity of Calcitriol That Contributes to Its Therapeutic and Chemopreventive Effects in Prostate Cancer

Abstract

Calcitriol exerts anti-proliferative and pro-differentiating effects in a number of tumors and malignant cells and its use as an anti-cancer therapy is currently being evaluated. Many 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. Our recent research reveals that calcitriol exhibits several anti-inflammatory actions that we believe contribute to its anti-cancer effects. In normal and malignant prostate epithelial cells calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the up-regulation of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs, and (iii) the decreasing of 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. The results of our clinical trial in men with early recurrent PCa indicate that the combination of high-dose weekly calcitriol with the non-selective NSAID naproxen slows the rate of rise (doubling time) of serum prostate specific antigen (PSA) levels in most patients indicating a slowing of disease progression. Calcitriol also increases the expression of mitogen-activated protein kinase phosphatase 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 in PCa through the inhibition of NFκB signaling in PCa cells. The discovery of these novel calcitriol-regulated molecular pathways reveal that calcitriol has anti-inflammatory actions, which in addition to its other anti-cancer effects, may play an important role in the prevention and/or treatment of cancer in general and PCa specifically.