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- Creators: Yang, Joanna
- Creators: Arizona State University
- 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
Thalidomide is a sedative drug introduced to European markets on 1 October 1957 after extensive testing on rodent embryos to ensure its safety. Early laboratory tests in rodent populations showed that pregnant rodents could safely use it, so doctors prescribed Thalidomide to treat morning sickness in pregnant women. However, in humans Thalidomide interfered with embryonic and fetal development in ways not observed in rodent tests. Pregnant women who take Thalidomide are at grater than normal risk for spontaneous abortion and for giving birth to children with developmental anomalies such as shortened, absent, or extra limbs, as well as a variety of heart, ear, and internal organ defects. The failure of rodent models to inform scientists of Thalidomide's teratogenicity in humans ignited debate about the proper use of cross-species testing during drug development.
ContributorsYang, Joanna (Author) / Tantibanchachai, Chanapa (Author) / LaTourelle, Jonathan J. (Editor) / Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia. (Publisher) / Arizona Board of Regents (Publisher)
Created2014-03-07
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