| Abstrakt: |
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 chapter describes recent research revealing that anti-inflammatory effects are an additional 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 upregulation 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 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 through the inhibition of nuclear factor kappa B (NFΚB) 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. [ABSTRACT FROM AUTHOR] |
