Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol)

Adorini, Luciano; Penna, Giuseppe; Amuchastegui, Susana; Cossetti, Chiara; Aquilano, Francesca; Mariani, Roberto; Fibbi, Benedetta; Morelli, Annamaria; Uskoković, Milan R.; Colli, Enrico; Maggi, Mario

doi:10.1016/j.jsbmb.2006.12.065

Cited by 71 publications

(46 citation statements)

References 36 publications

(41 reference statements)

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“…These observations also suggest that other vitamin D derivatives having androgen-independent antiproliferative effects that do not modulate UGT enzymes may display stronger antiproliferative effects in LNCaP cells than calcitriol. Interestingly, a recent study revealed that vitamin D 5, a 1a-hydroxylated metabolite of vitamin D, showed significantly different molecular effects in bone and prostate cells (40,42,43). In particular, this compound is a stronger reducer of LNCaP cell proliferation than calcitriol, and it fails to activate AR in this cell line (43).…”

Section: Discussionmentioning

confidence: 99%

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Kaeding

Bélanger

Caron

et al. 2008

Molecular Cancer Therapeutics

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Calcitriol (1A,25-dihydroxyvitamin D 3 ), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3A-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15-and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells. [Mol Cancer Ther 2008;7(2):380 -90]

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Section: Discussionmentioning

confidence: 99%

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Kaeding

Bélanger

Caron

et al. 2008

Molecular Cancer Therapeutics

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“…In addition, nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B) signaling, a major mediator of the immune response, is inhibited in various cancers by 1,25(OH) 2 D 3 by acting on different members of this pathway (304, 455) (FIGURE 7). A suppressed production of inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, IL-17, and TNF-␣ is consistently demonstrated in in vitro and in vivo cancer models (5,162,240,330) (FIGURE 7). In a preclinical SMAD3 knockout model of colitis and colon cancer, Meeker et al (304) showed that a high vitamin D diet decreases NF-B activation in colonic epithelial cells, which is reflected by decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines during initiation of carcinogenesis (304).…”

Section: D) Effects On Inflammation In Cancermentioning

confidence: 94%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,435

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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“…The findings showing that VDRs are expressed in normal prostate tissue, in benign prostate hyperplasia (BPH), and in prostate cancer cells suggest that BPH and prostate cancer (PCa) may represent potential targets for VDR ligands (Adorini et al, 2007;Crescioli et al, 2002;Hendrickson et al, 2011;Krill et al, 2001;Munetsuna et al, 2011;Swami et al, 2011). Several experimental observations have highlighted the fact that VDR ligands may exert numerous effects on prostate cancer cells including cellcycle arrest in the G0/G1 phase, apoptosis, and interaction with androgen-mediated signaling (Guzey et al, 2002;Nagpal et al, 2005;Zhuang & Burnstein, 1998).…”

Section: Effects Of Vitamin D On Prostate Cancer Cellsmentioning

confidence: 99%

“…Interestingly, Danielsson et al (1998) reported that CB1093 appeared to be very effective in inducing apoptosis in the early stage in the WM1341 melanoma cell line, but not in the advanced stage in MeWo melanoma cell line. Other studies examined the effects induced by BXL-628 analogue or Elocalcitol in benign prostatic hyperplasia and in prostate cancer cells (Adorini et al, 2007;Penna et al, 2009;Tiwari, 2009). The results of these studies indicated that the main mechanism appears to be related to the inhibition of growth factors and to the interleukin-8 (IL-8) production via a decrease in COX-2 and PGE2 synthesis (Adorini et al, 2007;Penna et al, 2009).…”

Section: Analogues Of 20-epi Vitamin Dmentioning

confidence: 99%

“…Other studies examined the effects induced by BXL-628 analogue or Elocalcitol in benign prostatic hyperplasia and in prostate cancer cells (Adorini et al, 2007;Penna et al, 2009;Tiwari, 2009). The results of these studies indicated that the main mechanism appears to be related to the inhibition of growth factors and to the interleukin-8 (IL-8) production via a decrease in COX-2 and PGE2 synthesis (Adorini et al, 2007;Penna et al, 2009). Elocalcitol was also able to inhibit the proliferation and invasiveness of prostate cancer cell line, DU145 by interfering with keratinocytes growth factor (KGF)-induced proliferation (Marchiani et al, 2006).…”

Section: Analogues Of 20-epi Vitamin Dmentioning

confidence: 99%

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Vitamin D in cancer chemoprevention

Giammanco¹,

Majo²,

Guardia

et al. 2015

Pharmaceutical Biology

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Context: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. Objective: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. Methods: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. Results and conclusion: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

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Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol)

Cited by 71 publications

References 36 publications

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Vitamin D in cancer chemoprevention

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