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lüll Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment Krishnan AV; Feldman DEndocr Relat Cancer 2010[Mar]; 17 (1): R19-38Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that calcitriol also exhibits multiple anti-inflammatory effects. First, calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, calcitriol increases the expression of mitogen-activated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-kappaB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.|Adenocarcinoma/*drug therapy/etiology/metabolism/pathology/*prevention & control[MESH]|Angiogenesis Inhibitors/pharmacology/therapeutic use[MESH]|Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use[MESH]|Anticarcinogenic Agents/*pharmacology/therapeutic use[MESH]|Antineoplastic Agents/*pharmacology/therapeutic use[MESH]|Apoptosis/drug effects[MESH]|Calcitriol/*pharmacology/therapeutic use[MESH]|Cell Line, Tumor/drug effects[MESH]|Clinical Trials as Topic[MESH]|Cyclooxygenase 2 Inhibitors/pharmacology/therapeutic use[MESH]|Cyclooxygenase 2/biosynthesis/genetics[MESH]|Dual-Specificity Phosphatases/biosynthesis/genetics[MESH]|Enzyme Induction/drug effects[MESH]|Gene Expression Regulation, Neoplastic/drug effects[MESH]|Humans[MESH]|Hydroxyprostaglandin Dehydrogenases/biosynthesis/genetics[MESH]|Male[MESH]|Mitogen-Activated Protein Kinase Phosphatases/biosynthesis/genetics[MESH]|NF-kappa B/antagonists & inhibitors[MESH]|Neoplasm Proteins/antagonists & inhibitors/biosynthesis/genetics[MESH]|Prostaglandins/metabolism[MESH]|Prostatic Neoplasms/*drug therapy/etiology/metabolism/pathology/*prevention & control[MESH]|Prostatitis/complications/drug therapy[MESH]|Receptors, Prostaglandin/biosynthesis/genetics[MESH] |