Non-hypercalcemic pharmacological aspects of vitamin D analogs

doi:10.1016/0006-2952(95)00121-F

Biochemical Pharmacology

Volume 50, Issue 5, 25 August 1995, Pages 577-583

https://doi.org/10.1016/0006-2952(95)00121-F Get rights and content

First page preview

Click to open first page preview

View PDF

References (39)

GR Williams et al.
Physiology of the steroid-thyroid nuclear receptor superfamily
Baillière's Clin Endocr Metab
(1994)
DD Bikle et al.
Regulation of keratinocyte growth, differentiation, and vitamin-D metabolism by analogs of 1,25-dihydroxyvitamin-D
J Invest Dermatol
(1993)
L Binderup
Immunological properties of vitamin D analogues and metabolites
Biochem Pharmacol
(1992)
L Binderup et al.
20-Epi-vitamin D₃ analogues: A novel class of potent regulators of cell growth and immune responses
Biochem Pharmacol
(1991)
AW Norman et al.
Structure-function studies of 1,25-dihydroxyvitamin D₃ and the vitamin D endocrine system. 1,25-Dihydroxy-pentadeuterio-previtamin D₃ (as a 6-s-cis analog) stimulates nongenomic but not genomic biological responses
J Biol Chem
(1993)
AW Norman et al.
Demonstration that 1β,25-dihydroxyvitamin-D₃; is an antagonist of the nongenomic but not genomic biological responses and biological profile of three A-ring diastereomers of 1α,25-dihydroxyvitamin-D₃
J Biol Chem
(1993)
J Ferrara et al.
Highly potent transcriptional activation by 16-ene derivatives of 1,25-dihydroxyvitamin D₃. Lack of modulation by 9-cis-retinoic acid of response to 1,25-dihydroxyvitamin D₃ or its derivatives
J Biol Chem
(1994)
KW Colston et al.
EB1089: A new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro
Biochem Pharmacol
(1992)
HM Xu et al.
1,25-Dihydroxyvitamin D₃ protects HL60 cells against apoptosis but down-regulates the expression of the bcl-2 gene
Exp Cell Res
(1993)
P Veyron et al.
Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice
Transpl Immunol
(1993)

C Fournier et al.

In vivo beneficial effects of cyclosporin A and 1,25-dihydroxyvitamin D₃ on the induction of experimental autoimmune thyroiditis

Clin Immunol Immunopathol

(1990)

M Inaba et al.

Partial protection of 1α-hydroxyvitamin D₃ against the development of diabetes induced by multiple low-dose streptozotocin injection in CD-1 mice

Metabolism

(1992)

E Mellanby et al.

Experimental investigation on rickets

Lancet

(1919)

HF DeLuca

Remembrance: Discovery of the vitamin D endocrine system

Endocrinology

(1992)

MR Walters

Newly identified actions of the vitamin-D endocrine system

Endocr Rev

(1992)

DD Bikle

Clinical counterpoint: Vitamin D: New actions, new analogs, new therapeutic potential

Endocr Rev

(1992)

Bouillon R, Okamura WH and Norman AW, Structure-function relationships in the vitamin D endocrine system. Endocr Rev,...

JW Pike

Vitamin D₃ receptors: Structure and function in transcription

Annu Rev Nutr

(1991)

PN MacDonald et al.

Evaluation of a putative vitamin D response element in the avian calcium binding protein gene

DNA Cell Biol

(1992)

Cited by (44)

Role of Vitamin D in uterine fibroid biology
2015, Fertility and Sterility
Citation Excerpt :
Thus, 1,400 IU is a possible nontoxic and effective treatment of uterine leiomyoma. Moreover, analogs of vitamin D3 have been successfully synthesized, and their antiproliferative properties with reduced hypercalcemic effect have been previously demonstrated (94–96). Our investigations with paricalcitol confirm these findings and suggest that vitamin D3 analogs could be potential candidates for an effective, safe, and noninvasive medical treatment option for uterine fibroids (92).
To provide a detailed summary of current scientific knowledge on uterine fibroids (leiomyomas) in vitro and in in vivo animal models, as well as to postulate the potential role of vitamin D3 as an effective, inexpensive, safe, long-term treatment option for uterine fibroids.
PubMed search articles were used to identify the most relevant studies on uterine fibroids, as well as effects of vitamin D3 on uterine fibroid cells and fibroid tumor growth in in vivo animal models.
University research laboratory.
Not applicable.
None.
Not applicable.
Despite numerous publications available on uterine fibroids, information about the role that vitamin D3 plays in the regulation of uterine fibroids is limited. Most of the recent vitamin D3–related studies on uterine fibroids were published from our group. Recent studies have demonstrated that vitamin D deficiency plays a significant role in the development of uterine fibroids. Our recent studies have demonstrated that vitamin D3 reduces leiomyoma cell proliferation in vitro and leiomyoma tumor growth in in vivo animal models. These results postulate the potential role of vitamin D3 for an effective, safe, nonsurgical medical treatment option for uterine fibroids.
This article reviews human and animal studies and uncovers new possibilities for understanding the vitamin D–based therapeutic option for an effective, safe, long-term treatment of uterine fibroids. On the basis of these results, a clinical trial with vitamin D3 or a hypocalcemic analog, paricalcitol, may be warranted for nonsurgical medical treatment of uterine fibroids.
The vitamin D analog, MART-10, represses metastasis potential via downregulation of epithelial-mesenchymal transition in pancreatic cancer cells
2014, Cancer Letters
Citation Excerpt :
Whereas, with the emergence of non-classical functions of vitamin D in the late 1970s, such as anti-proliferation, anti-angiogenesis, pro-apoptosis, pro-differentiation, and anti-inflammation [8–15], numerous evidence has demonstrated the anti-tumor effect of 1α,25(OH)2D3, the active form of vitamin D. However, the clinical application of systemic administration of 1α,25(OH)2D3 to treat cancer is restricted by its lethal side effect of hypercalcemia. In an effort to avoid this side effect while to keep or even strengthen the anti-tumor effect, thousands of vitamin D analogs have been created [16–18]. Some of the analogs have been shown to exert potent anti-tumor effect in vitro and in vivo and even been applied in clinical trials.
Pancreatic cancer (PDA) is a devastating disease and there is no effective treatment available at present. To develop new regiments against PDA is urgently needed. Previously we have shown that vitamin D analog, MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), exerted potent antiproliferative effect on PDA in vitro and in vivo without causing hypercalcemia. Since metastasis is the major cause of PDA-related death, we therefore investigate the anti-metastasis effect of MART-10 on PDA. Our results showed that both 1α,25(OH)₂D₃ and MART-10 repressed migration and invasion of BxPC-3 and PANC cells with MART-10 much more potent than 1α,25(OH)₂D₃. 1α,25(OH)₂D₃ and MART-10 inhibited epithelial–mesenchymal transition (EMT) in pancreatic cancer cells through downregulation of Snail, Slug, and Vimentin expression in BxPC-3 and PANC cells. MART-10 further blocked cadherin switch (from E-cadherin to N-cadherin) in BxPC-3 cells. The F-actin synthesis in the cytoplasm of BxPC-3 cells was also repressed by 1α,25(OH)₂D₃ and MART-10 as determined by immunofluorescence stain. Both 1α,25(OH)₂D₃ and MART-10 decreased MMP-2 and -9 secretion in BxPC-3 cells as determined by western blot and zymography. Collectively, MART-10 should be deemed as a promising regimen against PDA.
Regression of endometrial implants treated with vitamin D<inf>3</inf> in a rat model of endometriosis
2013, European Journal of Pharmacology
Citation Excerpt :
This constitutes a major problem with its in vivo use (Van Etten et al., 2002). Fortunately, synthetic analogs of vitamin D3 that have similar immunomodulatory activity, but do not have its effects on calcium or bone metabolism (Bouillon et al., 1995). These analogs may prove useful in treating inflammatory diseases such as endometriosis in future.
Endometriosis is one of the most frequent gynecological diseases. In addition to their side effects, available medical therapies may decrease fertility. Current understanding of endometriosis focuses on the role of the immune system in its pathophysiology. Recent research shed light on the immunomodulatory effect of vitamin D₃. Thus, this study was designed to study the effect of vitamin D₃ on regression of endometriotic implants in a rat surgical model. Vitamin D₃ reduced cyst cross sectional area by 48.8%. Histologically, vitamin D treatment produced fibrosis as well as apoptosis in the stroma. The results of the present study suggest that vitamin D₃ administration may have a beneficial effect in treating endometriosis.
19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D <inf>3</inf> (MART-10) is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells
2011, Steroids
Citation Excerpt :
Since the pro-differentiation and anti-proliferative characters of 1α,25(OH)2D3 were first recognized three decades ago by Suda and co-workers [11], abundant studies have demonstrated the anti-tumor effect of 1α,25(OH)2D3 on a variety of cancer cells, including prostate [12,13], colon [14], breast [15], ovarian [16], pancreas [17,18], and liver [19,20]. To avoid the hypercalcemic side effect of 1α,25(OH)2D3, which hinders its clinical application, analogs of 1α,25(OH)2D3 have been created with an effort to maintain or potentiate anti-tumor effect while having less- or non-calcemic characteristic [21,22]. Among the analogs, EB1089 and CB1093 have been shown to suppress the growth of HCC in vitro [19,23].
The discovery that the active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)₂D] can modulate cellular proliferation and differentiation of cancer cells has led to its potential application as a chemotherapeutic agent to treat a variety of cancers. However, the use of 1α,25(OH)₂D is limited due to its lethal side effect of hypercalcemia upon systemic administration. To overcome this drawback, numerous analogs have been synthesized. In this report, we examined the anti-proliferative activity of a new analog, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃ (MART-10), in HepG2 liver cancer cells, and studied the potential mechanisms mediating this action. We found that MART-10 exhibited approximately 100-fold greater activity than 1α,25(OH)₂D₃ in inhibiting HepG2 cell proliferation as determined by cell number counting method. MART-10 was also approximately 100-fold more potent than 1α,25(OH)₂D₃ in the upregulation of p21 and p27, that in turn arrested HepG2 cells at the G₀/G₁ phase to a greater extent. Given that no active caspase 3 was detected and treatment with 1α,25(OH)₂D₃ or MART-10 did not further increase the fractions of apoptotic and necrosis cells over the controls, the growth-inhibitory effect of 1α,25(OH)₂D₃ and MART-10 on HepG2 cells may not involve apoptosis. Overall, our findings suggest that MART-10 is a good candidate as a novel therapeutic regimen against liver cancer. Further pre-clinical studies using animal models and the subsequent human clinical trials are warranted.
Novel cytotoxic and biological agents for prostate cancer: Where will the money be in 2005?
2005, European Journal of Cancer
In 2004, docetaxel-based chemotherapy became the first treatment capable of extending life in androgen-independent prostate cancer. The era of therapeutic nihilism in this disease has thus been put to rest and a broad range of agents is being tested with the goal of improving on the successes of 2004. Lessons learned from other tumour types will need to be applied to prostate cancer in order to harness the bounty of available ideas. Target amplification or activating mutations and not merely the presence of a target are likely to be important to the success of targeted agents. Thus, the promise of the current crop of targeted agents is most likely to be realised when pursued in the context of well-credentialed targets and tested in highly translational clinical trials that are capable not only of assessing tumour response, but also of evaluating the status of the targeted pathway. The most promising agents in clinical development are reviewed.
Characterization of five 19-nor-analogs of 1α,25(OH) <inf>2</inf>-Vitamin D<inf>3</inf> with 20-cyclopropyl-modified side-chains: Implications for ligand binding and calcemic properties
2004, Journal of Steroid Biochemistry and Molecular Biology
The steroid hormone 1α,25(OH)₂-Vitamin D₃ [1α,25(OH)₂D₃] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1α,25(OH)₂D₃, can stimulate transcription of a wide variety of genes. The synthesis of 1α,25(OH)₂D₃ analogs allows the study of structure–function relationships between ligand and the VDR. 1α,25(OH)₂D₃ is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1α,25(OH)₂D₃ analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F₆-19-nor-1α,25(OH)₂D₃] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC₅₀ ∼10 pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.

View all citing articles on Scopus

View full text

CommentaryNon-hypercalcemic pharmacological aspects of vitamin D analogs

First page preview

Baillière's Clin Endocr Metab

J Invest Dermatol

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Pharmacol

Exp Cell Res

Transpl Immunol

Clin Immunol Immunopathol

Metabolism

Experimental investigation on rickets

Lancet

Remembrance: Discovery of the vitamin D endocrine system

Endocrinology

Newly identified actions of the vitamin-D endocrine system

Endocr Rev

Clinical counterpoint: Vitamin D: New actions, new analogs, new therapeutic potential

Endocr Rev

Vitamin D3 receptors: Structure and function in transcription

Annu Rev Nutr

Evaluation of a putative vitamin D response element in the avian calcium binding protein gene

DNA Cell Biol

Commentary
Non-hypercalcemic pharmacological aspects of vitamin D analogs

Vitamin D₃ receptors: Structure and function in transcription