title: Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment.
abstract: Calcitriol, 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.
authors.affiliation: Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5103, USA.
authors.forename: Aruna V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D002986:Clinical Trials as Topic; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011453:Prostaglandins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011472:Prostatitis / Q000150:complications / Q000188:drug therapy; D011982:Receptors, Prostaglandin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; D002117:Calcitriol