Inhibition of prostaglandin synthesis and actions contributes to the beneficial effects of calcitriol in prostate cancer

Krishnan, Aruna V.; Srinivas, Sandy; Feldman, David

doi:10.4161/derm.1.1.7106

Cited by 16 publications

(15 citation statements)

References 70 publications

(97 reference statements)

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“…Changes in PSA doubling time (PSA-DT) post intervention were compared to baseline PSA-DT values. A prolongation of the PSA-DT was achieved in 75% of the patients suggesting a potential beneficial effect of the combination therapy (Krishnan et al 2009.…”

Section: Clinical Studies Of Calcitriol In Pcamentioning

confidence: 90%

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

Krishnan¹,

Feldman²

2010

Endocrine-Related Cancer

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128

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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.

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Section: Clinical Studies Of Calcitriol In Pcamentioning

confidence: 90%

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

Krishnan¹,

Feldman²

2010

Endocrine-Related Cancer

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128

118

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“…These findings led to a clinical trial combining the NSAID naproxen with calcitriol in men with early recurrent prostate cancer. The results indicate that the combination slows the rate of rise of prostate-specific antigen in most patients [57]. Silibinin, a natural flavonoid, has been shown to have potent cancer chemopreventive efficacy against colon carcinogenesis in an animal model [58].…”

Section: Is the Down-regulation Of 15-pgdh In The Tumors Due To Transmentioning

confidence: 97%

Prostaglandin catabolic enzymes as tumor suppressors

Tai

2011

Cancer Metastasis Rev

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15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key prostaglandin catabolic enzyme catalyzing the oxidation and inactivation of prostaglandin E(2) (PGE(2)) synthesized from the cyclooxygenase (COX) pathway. Accumulating evidence indicates that 15-PGDH may function as a tumor suppressor antagonizing the action of COX-2 oncogene. 15-PGDH has been found to be down-regulated contributing to elevated levels of PGE(2) in most tumors. The expression of 15-PGDH and COX-2 appears to be regulated reciprocally in cancer cells. Down-regulation of 15-PGDH in tumors is due, in part, to transcriptional repression and epigenetic silencing. Numerous agents have been found to up-regulate 15-PGDH by down-regulation of transcriptional repressors and by attenuation of the turnover of the enzyme. Up-regulation of 15-PGDH may provide a viable approach to cancer chemoprevention. Further catabolism of 15-keto-prostaglandin E(2) is catalyzed by 15-keto-prostaglandin-∆(13)-reductase (13-PGR), which also exhibits LTB(4)-12-hydroxydehydrogenase (LTB(4)-12-DH) activity. 13-PGR/LTB(4)-12-DH behaves as a tumor suppressor as well. This review summarizes current knowledge of the expression and function of 15-PGDH and 13-PGR/LTB(4)-12-DH in lung and other tissues during tumor progression. Future directions of research on these prostaglandin catabolic enzymes as tumor suppressors are also discussed.

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“…The therapy was well tolerated by most patients. A prolongation of the PSA doubling time was achieved in 75% of the patients, suggesting a beneficial effect of the combination therapy [366,367].…”

Section: Calcitriol As a Part Of Combination Therapymentioning

confidence: 95%

“…However, in comparison to some COX-2-selective inhibitors, nonselective NSAIDs such as naproxen may be associated with fewer cardiovascular adverse effects [364,365]. Preclinical data [239] suggest that the combination of calcitriol with a non-selective NSAID would be a useful therapeutic approach in PCa that would allow both drugs to be used at reduced dosages leading to increased efficacy as well as improved cardiovascular safety [359,366]. As discussed in "Clinical trials," below, a phase II trial evaluating the combination of the nonselective NSAID naproxen and high-dose calcitriol in patients with early recurrent PCa demonstrated some benefit in terms of reduction in PSA doubling time [367].…”

Section: Calcitriol and Non-steroidal Anti-inflammatory Drugsmentioning

confidence: 97%