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- All Subjects: Bexarotene
- All Subjects: Immunology
- Creators: Marshall, Pamela
- Creators: Jurutka, Peter
- Status: Published
Description
Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
Description
Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.
ContributorsSeto, David Hua (Author) / Marshall, Pamela (Thesis director) / Wagner, Carl (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
Description
Bexarotene (Bex) is a FDA-approved drug used to treat cutaneous T-cell lymphoma (CTCL). It binds with high affinity to the retinoid-X-receptor (RXR), a nuclear receptor implicated in numerous biological pathways. Bex may have the potential to attenuate estrogenic activity by acting as an estrogen receptor alpha (ERα) signaling antagonist, and can therefore be used to treat ERα-positive cancers, such as breast cancer. Using dual luciferase reporter assays, real-time qRT-PCR, and metabolic proliferation assays, the anti-estrogenic properties of Bex were ascertained. However, since Bex produces numerous contraindications, select novel RXR drug analogs were also evaluated. Results revealed that, in luciferase assays, Bex could significantly (P < 0.01) inhibit the transcriptional activity of ERα, so much so that it rivaled ER pan-antagonist ZK164015 in potency. Bex was also able to suppress the proliferation of two breast cancer cell models, MCF-7 and T-47D, and downregulate the expression of an estrogen receptor target gene (A-myb), which is responsible for cell proliferation. In addition, novel analogs A30, A33, A35, and A38 were evaluated as being more potent at inhibiting ERE-mediated transcription than Bex at lower concentrations. Analogs A34 and A35 were able to suppress MCF-7 cell proliferation to a degree comparable to that of Bex. Inhibition of T-47D cell proliferation, by contrast, was best achieved by analogs A34 and A36. For those with ERα – positive breast cancer who are refractory to current chemotherapeutics used to treat breast cancer, Bex and its analogs may prove to be useful alternative options.
ContributorsBains, Supreet (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application of novel analogs of Bexarotene (RXR agonist), MeTC7 (a new potent VDR antagonist), and vitamin D as possible therapeutics for cancer and Alzheimer’s disease.
ContributorsHong, Jennifer (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023
Description
The retinoid-X receptor (RXR) can form heterodimers with both the retinoic-acid
receptor (RAR) and vitamin D receptor (VDR). The RXR/RAR dimer is activated by ligand all
trans retinoic acid (ATRA), which culminates in gut-specific effector T cell migration. Similarly,
the VDR/RXR dimer binds 1,25(OH)2D3 to cause skin-specific effector T cell migration.
Targeted migration is a potent addition to current vaccines, as it would induce activated T cell
trafficking to appropriate areas of the immune system and ensure optimal stimulation (40).
ATRA, while in use clinically, is limited by toxicity and chemical instability. Rexinoids
are stable, synthetically developed ligands specific for the RXR. We have previously shown that
select rexinoids can enhance upregulation of gut tropic CCR9 receptors on effector T cells.
However, it is important to establish whether these cells can actually migrate, to show the
potential of rexinoids as vaccine adjuvants that can cause gut specific T cell migration.
Additionally, since the RXR is a major contributor to VDR-mediated transcription and
epidermotropism (15), it is worth investigating whether these compounds can also function as
adjuvants that promote migration by increasing expression of skin tropic CCR10 receptors on T
cells.
Prior experiments have demonstrated that select rexinoids can induce gut tropic migration
of CD8+ T cells in an in vitro assay and are comparable in effectiveness to ATRA (7). The effect
of rexinoids on CD4+ T cells is unknown however, so the aim of this project was to determine if
rexinoids can cause gut tropic migration in CD4+ T cells to a similar extent. A secondary aim
was to investigate whether varying concentrations in 1,25-Dihydroxyvitamin D3 can be linked to
increasing CCR10 upregulation on Jurkat CD4+ T cells, with the future aim to combine 1,25
Dihydroxyvitamin D3 with rexinoids.
These hypotheses were tested using murine splenocytes for the migration experiment, and
human Jurkat CD4+ T cells for the vitamin D experiment. Migration was assessed using a
Transwell chemotaxis assay. Our findings support the potential of rexinoids as compounds
capable of causing gut-tropic migration in murine CD4+ T cells in vitro, like ATRA. We did not
observe conclusive evidence that vitamin D3 causes upregulated CCR10 expression, but this
experiment must be repeated with a human primary T cell line.
receptor (RAR) and vitamin D receptor (VDR). The RXR/RAR dimer is activated by ligand all
trans retinoic acid (ATRA), which culminates in gut-specific effector T cell migration. Similarly,
the VDR/RXR dimer binds 1,25(OH)2D3 to cause skin-specific effector T cell migration.
Targeted migration is a potent addition to current vaccines, as it would induce activated T cell
trafficking to appropriate areas of the immune system and ensure optimal stimulation (40).
ATRA, while in use clinically, is limited by toxicity and chemical instability. Rexinoids
are stable, synthetically developed ligands specific for the RXR. We have previously shown that
select rexinoids can enhance upregulation of gut tropic CCR9 receptors on effector T cells.
However, it is important to establish whether these cells can actually migrate, to show the
potential of rexinoids as vaccine adjuvants that can cause gut specific T cell migration.
Additionally, since the RXR is a major contributor to VDR-mediated transcription and
epidermotropism (15), it is worth investigating whether these compounds can also function as
adjuvants that promote migration by increasing expression of skin tropic CCR10 receptors on T
cells.
Prior experiments have demonstrated that select rexinoids can induce gut tropic migration
of CD8+ T cells in an in vitro assay and are comparable in effectiveness to ATRA (7). The effect
of rexinoids on CD4+ T cells is unknown however, so the aim of this project was to determine if
rexinoids can cause gut tropic migration in CD4+ T cells to a similar extent. A secondary aim
was to investigate whether varying concentrations in 1,25-Dihydroxyvitamin D3 can be linked to
increasing CCR10 upregulation on Jurkat CD4+ T cells, with the future aim to combine 1,25
Dihydroxyvitamin D3 with rexinoids.
These hypotheses were tested using murine splenocytes for the migration experiment, and
human Jurkat CD4+ T cells for the vitamin D experiment. Migration was assessed using a
Transwell chemotaxis assay. Our findings support the potential of rexinoids as compounds
capable of causing gut-tropic migration in murine CD4+ T cells in vitro, like ATRA. We did not
observe conclusive evidence that vitamin D3 causes upregulated CCR10 expression, but this
experiment must be repeated with a human primary T cell line.
ContributorsDebray, Hannah Zara (Co-author) / Debray, Hannah (Co-author) / Blattman, Joseph (Thesis director) / Jurutka, Peter (Committee member) / Manhas, Kavita (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Exposure of harmful ultraviolet rays (UV) is a great concern in many locations around the world, as skin diseases and cancer continue to surge. With the number of skin cancer skyrocketing past all the types of known cancers, a vast majority of cases are reported daily. When the skin is exposed to UVA or UVB radiation, primarily from the sun, the UV radiation damages the DNA within the cells, which results in skin cancer. However, most damaged DNA of cells can undergo nucleotide excision repair. This involves a nuclease molecule that cuts the damaged bases. Preliminary research has developed other ways of repairing DNA damage in cells by implementing organic compounds. An organic chemical such as, ferulic acid has the ability to aid the mechanisms involved in nucleotide excision repair that takes place in your cells after DNA damage.
To test this, Saccharomyces cerevisiae was utilized. This is a primary model used in most medicinal studies due to the resemblance to human cells. This study evaluates the effect of ferulic acid, concentrations on ultraviolet radiated Rad 1 (mutant) and HB0 (wild type) yeast cells. The yeast strains were grown in two different concentrations for ferulic acid and treated with long-wave UV light under 30 seconds, 45 seconds, and 60 seconds. It is observed that, Rad 1 had heavier growth in the presence of high concentration of ferulic acid after UV treatment than HB0. But, HB0 yeast had heavier growth in the presence of lower concentrations of ferulic acid after UV treatment. Ferulic acid concentrations of 1 mM can influence cell repair after UV application by mRNA expression during nucleotide excision repair and higher absorption of UV.
To test this, Saccharomyces cerevisiae was utilized. This is a primary model used in most medicinal studies due to the resemblance to human cells. This study evaluates the effect of ferulic acid, concentrations on ultraviolet radiated Rad 1 (mutant) and HB0 (wild type) yeast cells. The yeast strains were grown in two different concentrations for ferulic acid and treated with long-wave UV light under 30 seconds, 45 seconds, and 60 seconds. It is observed that, Rad 1 had heavier growth in the presence of high concentration of ferulic acid after UV treatment than HB0. But, HB0 yeast had heavier growth in the presence of lower concentrations of ferulic acid after UV treatment. Ferulic acid concentrations of 1 mM can influence cell repair after UV application by mRNA expression during nucleotide excision repair and higher absorption of UV.
ContributorsSabir, Zhino Lashkry (Author) / Marshall, Pamela (Thesis director) / Quaranta, Kimberly (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-12
Description
Mucosal membranes represent a major site of pathogen transmission and cancer development. Enhancing T cell migration to mucosal surfaces could improve immune-based therapies for these diseases, yielding better clinical outcomes. All-trans-retinoic acid (ATRA) is a biologically active form of vitamin A that has been shown to increase T cell migration to mucosal sites, however its therapeutic use is limited by its toxicity potential and unstable nature. ATRA-related compounds with lower toxicity and higher stability were assessed for their ability to induce similar immune migration effects as ATRA, using in vitro and in vivo model systems. Chapter 2 summarizes the first project, in which synthetic, ATRA-like compounds called rexinoids were used to modulate T cell expression of mucosal homing proteins chemokine receptor 9 (CCR9) and integrin alpha 4 beta 7 (α4β7), and alter their physical migration in vitro. Several rexinoids independently mimicked the activity of ATRA to enhance protein expression and migration, while others worked synergistically with subtoxic doses of ATRA to produce similar results. Furthermore, rexinoid administration in vivo was well-tolerated by animal models, a finding not seen with ATRA.
Chapter 3 focuses on the second project, where plasmids containing ATRA-synthesizing proteins were assessed for their in vivo ability to act as mucosal vaccine adjuvants and enhance T cell migration to mucosal sites during DNA vaccination. Though increased mucosal migration was seen with use of the adjuvant plasmids, these findings were not determined to be significant. Immune-mediated protection following viral challenge was also not determined to be significant in animal models receiving both vaccine and adjuvant plasmids.
The data shows that several novel rexinoids may possess enhanced clinical utility compared to ATRA, lending support for their use in immunotherapeutic approaches towards mucosal maladies. While the potential mucosal vaccine adjuvants did not show great significance in enhancing T cell migration or viral protection, further optimization of the model system may produce better results. This work helps advance knowledge of immune cell trafficking to afflicted mucosal regions. It can be used as a basis for understanding migration to other body areas, as well as for the development of better immune-based treatments.
ContributorsManhas, Kavita Rani (Author) / Blattman, Joseph (Thesis advisor) / Marshall, Pamela (Committee member) / Lake, Douglas (Committee member) / Ugarova, Tatiana (Committee member) / Arizona State University (Publisher)
Created2022
Description
Our gut microbiome is a dynamic and complex community of microorganisms that play a vital role in our immune system and metabolism. Probiotics have gained significant traction in the health and scientific communities due to their potential health benefits particularly in our gut microbiome. A particular probiotic organism that is already known to beneficially aid in metabolism, primarily glucose metabolism is the bacteria Lactobacillus acidophilus. Due to most probiotic foods and supplements being developed using multiple strains and species, it is of interest to quantify the potential synergistic abilities of the two most used species of probiotics when used in combination: the bacteria Lactobacillus acidophilus and the yeast Saccharomyces boulardii. With the rise of metabolic disorders and the price of synthetic insulin in the United States, identifying novel approaches to regulate glucose levels could offer alternate or complementary therapies.
The objective of this study was to explore any potential synergistic effects of a co-culture of S. boulardii and L. acidophilus in metabolizing dietary glucose. Probiotic supplements are typically consumed in the morning during breakfast, therefore, to replicate this process and as a source of dietary glucose, a super food mix consisting of white bread, orange juice, and one whole egg was prepared. After both probiotic organisms had been revived, they were thoroughly mixed with 1 ml of the super food mix and 1 ml of a stomach acid solution both individually and in co-culture. Total glucose levels [mg/dL] in each incubation were measured using a glucose colorimetric detection kit. In this ‘proof-of-concept' experiment, the introduction of both S.boulardii and L.acidophilus into an in vitro stomach incubation caused glucose levels to decrease by 25.6%. Although there was a marked decrease, more testing is required to determine the statistical significance. These experiments do show some promise of a positive collaborative effect between these microorganisms in reducing GI levels of glucose.
ContributorsBrassil, Catherine (Author) / Marshall, Pamela (Thesis director) / Schulte, Meredith (Committee member) / Barrett, The Honors College (Contributor) / College of Health Solutions (Contributor)
Created2024-05