Anti-Tumor Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D Analogs

Bemd, Gert-Jan C.M. van den; Pols, Huibert A. P.; Leeuwen, Johannes P.T.M. van

doi:10.2174/1381612003400498

Cited by 60 publications

(38 citation statements)

References 136 publications

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“…28) Many vitamin D analogues showed anti-cancer activity in vitro using human cultured cell lines, however, some of them did not possess such activity in vivo. 29,30) For the reasons of this difference, metabolic rate, stability in blood, binding ability to DBP, and other unknown factors affect to the activity of in vivo study. 10,31) In addition, calcemic action, immunosupressive effect, and so on would be provoked when vitamin D analogues are administrated to animal host.…”

Section: Discussionmentioning

confidence: 99%

Biological Activities of 2.ALPHA.-Substituted Analogues of 1.ALPHA.,25-Dihydroxyvitamin D3 in Transcriptional Regulation and Human Promyelocytic Leukemia (HL-60) Cell Proliferation and Differentiation

Takahashi

Nakagawa

Suhara

et al. 2006

Biological & Pharmaceutical Bulletin

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The physiologically active form of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 (1)), regulates calcium metabolism in mammals. The 1a,25(OH) 2 D 3 -liganded vitamin D receptor (VDR), 1) which is a member of the nuclear receptor superfamily, 2,3) heterodimerizes with the retinoid X receptor (RXR), 4) and this complex subsequently binds to a specific DNA sequence, the vitamin D-responsive element (VDRE), to induce gene transcription. 5) 1a,25(OH) 2 D 3 (1) has clinically been used for the treatment of cancers, 6) psoriasis 7,8) and immune disorders.9) The major limitation of 1a,25(OH) 2 D 3 for its clinical use is that it causes hypercalcemia.10) For this reason, low-calcemic 1a,25(OH) 2 D 3 analogues having side-chain modifications have been extensively studied.11) An analogue which substituted a methyl group at the 2a-position of 1a,25(OH) 2 D 3 enhanced its VDR affinity and the differentiation of HL-60 cells.12) Furthermore, 20-epimerization of 1a,25(OH) 2 D 3 strongly increased biological activity, 13,14) and double modification of 20-epimerization and 2a-methyl substitution resulted in a large increase of biological activity.15) Suhara et al. have reported that as the chain length at the 2a-position became longer, the more biological activities decreased in 2a-alkyl analogues, whereas these activities increased in 2a-hydroxyalkyl analogues. 16)Regarding 2-position substitution, the biological evaluation of a series of 2b-substituted analogues at the molecular level, with regard to the structural differences of alkyl, alkenyl, hydroxyalkyl, hydroxyalkoxy, alkoxy, hydroxyl and chloro substituents at the 2b-position of 1a,25(OH) 2 D 3 has been reported.17) It is well known that 1a,25(OH) 2 D 3 (1) inhibits the proliferation of promyelocytic leukemia cells and differentiates these cells to macrophages. 18,19) 1a,25(OH) 2 D 3 (1) has been shown to arrest the cell cycle at the G1 phase in malignant cells including leukemic cells and breast cancer cells.20,21) Therefore, we examined anticancer activity and differentiation-inducing activity of 1a,25(OH) 2 D 3 (1) and its analogues using human promyelocytic leukemia HL-60 cells. To clarify further biological activities of those analogues, we evaluated transactivation potency in rat-25-hydroxyvitamin D 3 -24-hydroxylase, osteocalcin, human VDR, VDR/RXR heterodimerization and the regulatory activity of the proliferation and differentiation of HL-60 cells. (3) hydroxyalkoxy-type analogues bearing a 2-hydroxyethoxy (O2C2), 3-hydroxypropoxy (O2C3), 4-hydroxybutoxy (O2C4) substituent. 23) All these compounds are depicted in Fig. 1. All analogues were dissolved in aldehyde-free absolute ethanol as stock solutions and stored at Ϫ35°C protected from light. All other reagents were of analytical grade and commercially available. MATERIALS AND METHODS VitaminBinding in 50 ml ethanol was mixed with increasing amounts of analogues (0.24-1000 ng) in 100 ml ethanol. Next, 1 ml of vitamin D-deficient rat serum diluted 1 : 70000 with freshly prepared barbital acetate buffe...

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Section: Discussionmentioning

confidence: 99%

Biological Activities of 2.ALPHA.-Substituted Analogues of 1.ALPHA.,25-Dihydroxyvitamin D3 in Transcriptional Regulation and Human Promyelocytic Leukemia (HL-60) Cell Proliferation and Differentiation

Takahashi

Nakagawa

Suhara

et al. 2006

Biological & Pharmaceutical Bulletin

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“…La 1,25-(OH)2D inhibe la prolifération de ces cellules en les bloquant en phase G1, via un effet activateur sur la synthèse des protéines p21 et p27 [9], module la production et l'action de proto-oncogènes, dont c-myc et c-fos, et favorise l'apoptose de certaines lignées tumorales en inhibant la production de la protéine Bcl-2 [10]. À ces effets positifs sur la prolifération-différenciation cellulaire s'ajoutent d'autres effets qui concourent à l'action antitumorale de la vitamine D, comme l'inhibition de l'angiogenèse péri-tumorale et celle du développement de métastases [11].…”

Section: Vitamine D Un Facteur Anti-cancéreux ?unclassified

“…Cependant, comme pour le traitement du psoriasis, l'application de ces résultats en clinique humaine est limitée par l'hypercalcémie résultant des fortes doses de 1,25-(OH)2D requises. Parmi les nombreux analogues peu hypercalcémiants de la vitamine D, plusieurs paraissent capables de prévenir ou retarder l'évolution de leucémies ou de cancers [2,10,11]. Ils sont donc de bons candidats pour une éventuelle utilisation en clinique humaine.…”

Section: Vitamine D Un Facteur Anti-cancéreux ?unclassified

La vitamine D : les nouvelles fonctions d’une ancienne vitamine

Garabédian¹

2000

OCL

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Summary: Vitamin D has long been known for its anti-rachitic properties. Recent research developements have pointed out its numerous in vitro and in vivo actions on the proliferationdifferentiation of epidermal and cancer cells, as well as on the recruitment, differentiation and activities of the immune cells. Emerging evidence for associations between the genotype of the vitamin D receptor and the susceptibility to develop cancer, tuberculosis, or auto-immune diseases, brings further support to the physiological importance of these actions, although they do not seem to reflect as essential functions as the classical ones on calcium homeostasis and skeletal mineralization. Nevertheless, these recently discovered actions have led to the development of new therapeutical tools for the treatment of psoriasis and investigations are currently under way to evaluate the possible beneficial effects of the active form of vitamin D, and of less hypercalcemic analogs, in patients with, or at risk for, colo-rectal, breast and prostate cancer, in patients with autoimmune diseases, and for prolonging allograft survival.

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“…The classic role of 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) 1 includes regulating the expression of genes involved in calcium and bone metabolism (1). In addition, the hormone is an important mediator of cell growth and differentiation (2,3).…”

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confidence: 99%

“…In addition, the hormone is an important mediator of cell growth and differentiation (2,3). In a large number of 1,25-(OH) 2 D 3 -dependent target genes, distinct vitamin D response elements (VDREs) have been identified that are composed of two hexameric half-sites separated by three base pairs (DR3-type VDRE).…”

mentioning

confidence: 99%

A Central Dinucleotide within Vitamin D Response Elements Modulates DNA Binding and Transactivation by the Vitamin D Receptor in Cellular Response to Natural and Synthetic Ligands

Bemd

Jhamai

Staal

et al. 2002

Journal of Biological Chemistry

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includes regulating the expression of genes involved in calcium and bone metabolism (1). In addition, the hormone is an important mediator of cell growth and differentiation (2, 3). In a large number of 1,25-(OH) 2 D 3 -dependent target genes, distinct vitamin D response elements (VDREs) have been identified that are composed of two hexameric half-sites separated by three base pairs (DR3-type VDRE). The vitamin D receptor (VDR)/retinoid X receptor (RXR) complex binds with defined polarity to these VDREs with the RXR occupying the distal half-site and the VDR the proximal half-site (4 -7).The spacing of the half-sites plays an important role in specifying the type of receptor pair that interacts with hormone response elements (7). There is considerable divergence in the nucleotide sequence of the distal and proximal half-site, which is attributable at least in part to redundancy in the consensus recognition motifs of the VDR and the RXR (8). The sequences of steroid hormone half-elements also influence the relative affinities for different steroid hormone receptors and thus may support receptor-specific gene activation by discriminating between different receptors (7). In addition, specific nucleotides in the VDRE appear to influence the conformation of bound VDR/RXR heterodimers, reflected by a VDRE-specific alteration in epitope accessibility (6). Furthermore, minor changes in the nucleotide sequence of half-elements can change a negative VDRE that suppresses transcription into a positive VDRE, which transactivates in a 1,25-(OH) 2 D 3 -dependent manner (9). The impact of minor changes in nucleotide sequences on receptor DNA binding is not restricted to VDR/ VDRE interactions, as evidenced by half-element point mutations that have been shown to alter the affinity (10) or identity of the cognate receptor (11).Two major 1,25-(OH) 2 D 3 -regulated genes are the two noncollagenous, osteoblast-derived bone matrix proteins osteocalcin and osteopontin. These genes have sequence variations in their VDREs (Refs. 12-14 and Table I). To gain insight into the biological relevance of nucleotide variation in naturally occurring VDREs for the action of 1,25-(OH) 2 D 3 and its potent analog KH1060 (15-18), we examined the binding and activity of the osteocalcin and osteopontin VDREs. The main finding of our study is that nucleotide differences between osteopontin and osteocalcin VDREs affect DNA binding and transactivation in response to 1,25-(OH) 2 D 3 and its potent analog, KH1060. Our findings show that the primary sequence of VDREs may influence the biological activities of natural and synthetic ligands that bind to the VDR. Finally, the strong biological potency of the analog KH1060 is only reflected by DNA binding of VDR/RXR heterodimers in the environment of nuclear proteins and not by the binding of in vitro synthesized VDR and RXR␣, underscoring the importance of a cellular context for ligand-induced DNA binding.

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Anti-Tumor Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D Analogs

Cited by 60 publications

References 136 publications

Biological Activities of 2.ALPHA.-Substituted Analogues of 1.ALPHA.,25-Dihydroxyvitamin D3 in Transcriptional Regulation and Human Promyelocytic Leukemia (HL-60) Cell Proliferation and Differentiation

Biological Activities of 2.ALPHA.-Substituted Analogues of 1.ALPHA.,25-Dihydroxyvitamin D3 in Transcriptional Regulation and Human Promyelocytic Leukemia (HL-60) Cell Proliferation and Differentiation

La vitamine D : les nouvelles fonctions d’une ancienne vitamine

A Central Dinucleotide within Vitamin D Response Elements Modulates DNA Binding and Transactivation by the Vitamin D Receptor in Cellular Response to Natural and Synthetic Ligands

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