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 mitogenactivated 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-kB 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.

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

“…Gastric cancer cells stably transfected with a 15-PGDH siRNA plasmid have a higher rate of proliferation, while stable transfection with a 15-PGDH cDNA suppressed both growth rate, clone formation, and soft agar colony formation of gastric cancer cells in vitro as well as tumor formation in athymic nude mice in vivo (39). Agents that specifically activate the expression of 15-PGDH have not been (40), and it has similar effects in prostate cancer (41). The requirement for the 15-PGDH pathway in mediating the antiproliferative and tumor suppressor actions of calcitriol is an area for further investigation.…”

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

“…For instance, paricalcitol treatment had suppressed COX-2 and NF-kB expression in colon, leukemic, and gastric cancer cells (10,44), and attenuated VEGF in renal diseases (45). In a constant line, vitamin D has intrinsically shown to inhibit NF-kB activity, reduce NF-kB protein levels, and downregulate a variety of NF-kB target genes in a variety of inflammatory and cancer cell types (46,47). Mechanistically, activation of VDR by vitamin D or its analogues results in VDR/IkB kinase beta protein (IKKb) physical interaction and stimulation/stabilization of the NF-kB inhibitory protein a (IkBa), all of which are responsible for blocking NF-kB binding to DNA and inhibition of its canonical activation pathway (47).…”

Prostate Cancer Dephosphorylation Atlas

“…Another DUSP that has been related to prostate cancer is DUSP10. DUSP10 presents antiinflammatory activity and its expression is increased after treatment with calcitriol, the hormonally active form of vitamin D. This results in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines (Nonn, et al, 2006;Krishnan & Feldman, 2010).…”