Highly active analogs of 1α,25-dihydroxyvitamin D3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways

Uskoković, Milan R.; Norman, Anthony W.; Manchand, Percy S.; Studzinski, George P.; Campbell, Moray J.; Koeffler, H. Phillip; Takeuchi, Atsuko; Siu-Caldera, Mei-Ling; Rao, Devara Sunita; Reddy, G. Satyanarayana

doi:10.1016/s0039-128x(00)00226-9

Cited by 55 publications

(45 citation statements)

References 16 publications

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“…For example, it has already been definitively demonstrated that metabolism of many superagonists is either slowed dramatically and/or the superagonists selectively undergo C24-metabolism, stopping at the 24-OH compound. All these superagonist metabolites maintain strong VDR agonist profiles [23] and therefore the parent compound and its metabolites collectively are believed to generate the superagonist response/ profile.…”

Section: Discussionmentioning

confidence: 99%

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New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Recently, we have developed a vitamin D sterol (VDS)-VDR conformational ensemble model. This model can be broken down into three individual, yet interlinked parts: a) the conformationally flexible VDS, b) the apo/holo-VDR helix-12 (H12) conformational ensemble, and c) the presence of two VDR ligand binding pockets (LBPs); one thermodynamically favored (the genomic pocket, Gpocket) and the other kinetically favored by VDSs (the alternative pocket, A-pocket). One focus of this study is to use directed VDR mutagenesis to 1) demonstrate H12 is stabilized in the transcriptionally active closed conformation (hVDR-c1) by three salt-bridges that span the length of H12 (cationic residues R154, K264 and R402), 2) to elucidate the VDR trypsin sites [R173 (hVDRc1), K413 (hVDR-c2) and R402 (hVDR-c3)] and 3) demonstrate the apo-VDR H12 equilibrium can be shifted. The other focus of this study is to apply the model to generate a mechanistic understanding to discrepancies observed in structure-function data obtained with a variety of 1α,25(OH) 2 -vitamin D 3 (1,25D) A-ring and side-chain analogs, and side-chain metabolites. We will demonstrate that these structure-function conundrums can be rationalized, for the most part by focusing on alterations in the VDS conformational flexibility and the elementary interaction between the VDS and the VDR A-and G-pockets, relative to the control, 1,25D.

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Section: Discussionmentioning

confidence: 99%

“…1A; C23 and C24-pathways [23]), share the 1,23S,25R-lac and KH VDR PSA profiles (e.g. abundance of hVDRwt-c3) and have reduced VDR RCI values.…”

Section: Introductionmentioning

confidence: 99%

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…[34][35][36][37]39 Here we translated these findings to in vivo conditions, using a syngeneic mouse leukemia tumor model. Our study shows for the first time that carnosic acid-rich rosemary extract and a low dose of a low-calcemic Ro25-4020 strongly cooperate in inhibiting tumorigenicity of WEHI-3B D 2 cells in Balb/c mice.…”

Section: Discussionmentioning

confidence: 99%

Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia

Sharabani

Izumchenko

Wang

et al. 2006

Intl Journal of Cancer

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1a,25-dihydroxyvitamin D 3 (1,25D 3 ) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D 3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D 2 murine myelomonocytic leukemia cells induced by 1 nM 1,25D 3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 lM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G01G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 lg Ro25-4020 in Balb/c mice bearing WEHI-3B D 2 tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 lg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia. ' 2006 Wiley-Liss, Inc.

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“…Among these, derivatives of vitamin D (deltanoids) have shown promise in pre-clinical studies (reviewed in refs. [1][2][3][4][5], but their use in the clinic has been limited by the possibility of life threatening hypercalcemia, induced by the classical action of vitamin D. 6,7 To reduce this danger, combinations of low concentrations of deltanoids with other compounds are being sought which increase the ability of deltanoids to induce differentiation of neoplastic cells, but have no effects on systemic calcium homeostasis. [8][9][10] Among these, several nonsteroidal anti-inflammatory agents have been reported to synergize with vitamin D 3 to increase differentiation of HL60 cells, a frequently used in vitro model of AML (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

Jamshidi

Zhang²,

Harrison³

et al. 2008

Cell Cycle

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Highly active analogs of 1α,25-dihydroxyvitamin D3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways

Cited by 55 publications

References 16 publications

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

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Highly active analogs of 1α,25-dihydroxyvitamin D3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways

Cited by 55 publications

References 16 publications

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

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Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia