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Article: Genomically anchored vitamin D receptor mediates an abundance of bioprotective actions elicited by its 1,25-dihydroxyvitamin D hormonal ligand.

Haussler, Mark R / Haussler, Carol A / Jurutka, Peter W

2023 Volume 123, Page(s) 313–383

Abstract: The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin ... ...

Abstract	The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin D
MeSH term(s)	Humans ; Calcium ; Ligands ; Parathyroid Hormone ; Receptors, Calcitriol/genetics
Chemical Substances	1,25-dihydroxyvitamin D (66772-14-3) ; Calcium (SY7Q814VUP) ; Ligands ; Parathyroid Hormone ; Receptors, Calcitriol ; VDR protein, human
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2022.12.008
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Article ; Online: Methods to Assess Activity and Potency of Rexinoids Using Rapid Luciferase-Based Assays: A Case Study with NEt-TMN.

Jurutka, Peter W / Wagner, Carl E

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2019, Page(s) 95–108

Abstract: This chapter outlines the materials, methods, and procedures for the in vitro biological evaluation of retinoid-X-receptor (RXR) agonists including 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), as well as ... ...

Abstract	This chapter outlines the materials, methods, and procedures for the in vitro biological evaluation of retinoid-X-receptor (RXR) agonists including 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), as well as several NEt-TMN analog compounds recently reported by our group. These methods have general applicability beyond this NEt-TMN case study, and can be employed to characterize and biologically evaluate other putative RXR agonists (rexinoids), and benchmarked against perhaps the most common rexinoid known as bexarotene (Bex), a drug awarded FDA approval for the treatment of cutaneous T-cell lymphoma in 1999 but that is also prescribed for non-small cell lung cancer and continues to be explored in multiple human cancer types. The side-effect profile of Bex treatment includes hypothyroidism and hypertriglyceridemia arising from the inhibition or activation of additional nuclear receptors that partner with RXR. Because rexinoids often exhibit selectivity for RXR activation, versus activating the retinoic-acid-receptor (RAR), rexinoid treatment avoids the cutaneous toxicity commonly associated as a side effect with retinoids. There are many examples of other potent rexinoids, where biological evaluation has contributed useful insight into qSAR studies on these compounds, often also benchmarked to Bex, as potential treatments for cancer. Because of differential pleiotropy in other pathways, even closely related rexinoids display unique side-effect and activity profiles. Notable examples of potent rexinoids in addition to Bex and NEt-TMN include CD3254, LGD100268, and 9-cis-UAB30. Indeed, the methods described herein to evaluate NEt-TMN and analogous rexinoids are generally applicable to a wider variety of potent, moderate, and even weak RXR ligands.In terms of in vitro biological evaluation, methods for a rapid and preliminary assessment of rexinoid activity are described by employing a biologically relevant, RXR-responsive element (RXRE)-mediated transcription assay in mammalian cells. In addition, a second, more sensitive assay is also detailed that utilizes activation of RXR-RXR homodimers in the context of a mammalian two-hybrid (M2H) luciferase assay. Methods for applying the M2H assay at different rexinoid concentrations are further described for the determination of EC
MeSH term(s)	Coumaric Acids/pharmacology ; Drug Evaluation, Preclinical ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Retinoid X Receptor alpha/agonists ; Retinoids/pharmacology ; Signal Transduction ; Tetrahydronaphthalenes/pharmacology
Chemical Substances	CD 3254 ; Coumaric Acids ; RXRA protein, human ; Retinoid X Receptor alpha ; Retinoids ; Tetrahydronaphthalenes
Language	English
Publishing date	2019-07-29
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9585-1_7
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Article ; Online: Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist: A Case Study with NEt-TMN.

Wagner, Carl E / Jurutka, Peter W

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2019, Page(s) 109–121

Abstract: The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino) ...

Abstract	The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.
MeSH term(s)	Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Drug Design ; Humans ; Molecular Structure ; Retinoid X Receptors/agonists ; Retinoid X Receptors/chemistry ; Structure-Activity Relationship ; Tetrahydronaphthalenes/chemical synthesis ; Tetrahydronaphthalenes/chemistry ; Tetrahydronaphthalenes/pharmacology
Chemical Substances	Antineoplastic Agents ; Retinoid X Receptors ; Tetrahydronaphthalenes
Language	English
Publishing date	2019-07-29
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9585-1_8
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Article ; Online: Dietary

Lu, Shun / Xu, Jing / Zhao, Zihao / Guo, Yuheng / Zhang, Hanwen / Jurutka, Peter W / Huang, Dechun / Cao, Chongjiang / Cheng, Shujie

Food & function

2023 Volume 14, Issue 23, Page(s) 10314–10328

Abstract: There is a need to explore combination therapy to improve the efficacy of immunotherapy for colorectal cancer through food probiotics. In this study, extracellular vesicles (EV) derived ... ...

Abstract	There is a need to explore combination therapy to improve the efficacy of immunotherapy for colorectal cancer through food probiotics. In this study, extracellular vesicles (EV) derived from
MeSH term(s)	Mice ; Animals ; Lacticaseibacillus rhamnosus ; CD8-Positive T-Lymphocytes ; Cell Death ; Immunotherapy ; Extracellular Vesicles ; Colorectal Neoplasms/drug therapy ; Probiotics
Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2612033-1
ISSN	2042-650X ; 2042-6496
ISSN (online)	2042-650X
ISSN	2042-6496
DOI	10.1039/d3fo02018e
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Article ; Online: Prediagnostic 25-Hydroxyvitamin D in Association with Cancer-specific and All-cause Mortality among Low-income, Non-Hispanic Black Americans with Colorectal Cancer.

Lawler, Thomas P / Khankari, Nikhil K / Shu, Xiao-Ou / Steinwandel, Mark / Cai, Qiuyin / Jurutka, Peter W / Zheng, Wei / Warren Andersen, Shaneda

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2023 Volume 32, Issue 8, Page(s) 1061–1068

Abstract: Background: Observational studies show high prediagnosis 25-hydroxyvitamin D is associated with lower mortality after colorectal cancer diagnosis. Results from clinical trials suggest vitamin D supplementation may improve outcomes among patients with ... ...

Abstract	Background: Observational studies show high prediagnosis 25-hydroxyvitamin D is associated with lower mortality after colorectal cancer diagnosis. Results from clinical trials suggest vitamin D supplementation may improve outcomes among patients with colorectal cancer. Most studies included few Black Americans, who typically have lower 25-hydroxyvitamin D. We evaluated associations between serum 25-hydroxyvitamin D and mortality after colorectal cancer diagnosis among Black American cases. Methods: Data arose from 218 Black Americans from the Southern Community Cohort Study diagnosed with colorectal cancer during follow-up (age 40-79 at enrollment). Prediagnostic 25-hydroxyvitamin D was measured at enrollment and categorized as deficient (<12 ng/mL), insufficient (12-19.9 ng/mL), or sufficient (≥20 ng/mL). Mortality was determined from the National Death Index. Cox proportional hazards were used to estimate HRs and 95% confidence intervals (CI) for associations between 25-hydroxyvitamin D and mortality. Results: As a continuous exposure, higher 25-hydroxyvitamin D was associated with overall mortality [HR = 0.79 (0.65-0.96) per-SD increase, Ptrend = 0.02] and colorectal cancer-specific mortality [HR = 0.83 (0.64-1.08), Ptrend = 0.16]. For overall mortality, associations were strongest among females [HR = 0.65 (0.42-0.92)], current smokers [HR = 0.61 (0.38-0.98)], and obese participants [HR = 0.47 (0.29-0.77)]. Compared with those with deficiency, participants with sufficient 25-hydroxyvitamin D had lower overall mortality after multivariable adjustment [HR: 0.61 (0.37-1.01)]. Conclusions: Prediagnosis 25-hydroxyvitamin D is inversely associated with overall and colorectal cancer-specific mortality among Black Americans with colorectal cancer. Correcting vitamin D deficiency may improve survival of these patients, particularly for obese individuals and smokers. Impact: Our results support including more Black Americans in trials of vitamin D supplementations to improve colorectal cancer outcomes.
MeSH term(s)	Adult ; Aged ; Female ; Humans ; Middle Aged ; Black or African American ; Cohort Studies ; Colorectal Neoplasms ; Obesity ; Vitamin D ; Vitamin D Deficiency ; Male
Chemical Substances	25-hydroxyvitamin D (A288AR3C9H) ; Vitamin D (1406-16-2)
Language	English
Publishing date	2023-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-23-0252
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Article ; Online: Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration

Manhas, Kavita R / Marshall, Pamela A / Wagner, Carl E / Jurutka, Peter W / Mancenido, Michelle V / Debray, Hannah Z / Blattman, Joseph N

Frontiers in immunology

2022 Volume 13, Page(s) 746484

Abstract: Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All- ...

Abstract	Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-
MeSH term(s)	Animals ; Cell Movement/drug effects ; Female ; Integrins/genetics ; Integrins/immunology ; Mice ; Mice, Inbred BALB C ; Mucous Membrane/metabolism ; Receptors, CCR/genetics ; Receptors, CCR/immunology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Tretinoin/pharmacology
Chemical Substances	CC chemokine receptor 9 ; Integrins ; Receptors, CCR ; integrin alpha4beta7 ; Tretinoin (5688UTC01R)
Language	English
Publishing date	2022-01-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.746484
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Article ; Online: EDITORIAL (Thematic Issue : Rexinoids).

Wagner, Carl E / Marshall, Pamela A / Jurutka, Peter W

Current topics in medicinal chemistry

2017 Volume 17, Issue 6, Page(s) 629–630

MeSH term(s)	Animals ; Humans ; Retinoid X Receptors/chemistry
Chemical Substances	Retinoid X Receptors
Language	English
Publishing date	2017-01-12
Publishing country	United Arab Emirates
Document type	Editorial
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802661706170111200835
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Article ; Online: Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25-Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor-23.

Haussler, Mark R / Livingston, Sarah / Sabir, Zhela L / Haussler, Carol A / Jurutka, Peter W

JBMR plus

2020 Volume 5, Issue 1, Page(s) e10432

Abstract: The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH) ...

Abstract	The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)
Language	English
Publishing date	2020-12-03
Publishing country	England
Document type	Journal Article
ISSN	2473-4039
ISSN (online)	2473-4039
DOI	10.1002/jbm4.10432
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Article ; Online: Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Warda, Ankedo / Staniszewski, Lech J P / Sabir, Zhela / Livingston, Sarah / Sausedo, Michael / Reshi, Sabeeha / Ron, Eyal / Applegate, Michael T / Haddad, Dena / Khamisi, Madleen / Marshall, Pamela A / Wagner, Carl E / Jurutka, Peter W

Cells

2023 Volume 12, Issue 21

Abstract: Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading ... ...

Abstract	Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.
MeSH term(s)	Humans ; Bexarotene/pharmacology ; Bexarotene/therapeutic use ; Tetrahydronaphthalenes/pharmacology ; Tetrahydronaphthalenes/therapeutic use ; Lymphoma, T-Cell, Cutaneous/metabolism ; Retinoid X Receptors/metabolism ; Skin Neoplasms/drug therapy
Chemical Substances	Bexarotene (A61RXM4375) ; Tetrahydronaphthalenes ; Retinoid X Receptors
Language	English
Publishing date	2023-11-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12212575
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Article ; Online: The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer.

Reich, Lyndsey A / Moerland, Jessica A / Leal, Ana S / Zhang, Di / Carapellucci, Sarah / Lockwood, Beth / Jurutka, Peter W / Marshall, Pamela A / Wagner, Carl E / Liby, Karen T

Scientific reports

2022 Volume 12, Issue 1, Page(s) 293

Abstract: Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell ...

Abstract	Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice, Transgenic ; Retinoid X Receptors/agonists ; Retinoid X Receptors/metabolism ; Signal Transduction ; Time Factors ; Tumor Burden/drug effects
Chemical Substances	Antineoplastic Agents ; Retinoid X Receptors
Language	English
Publishing date	2022-01-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-04415-0
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