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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Bexarotene (Figure 6.106), marketed as TargtretinTM, has a similar structure to tretinoin and alitretinoin, and was approved by the FDA and EMA in 1999 and 2001, respectively, as a treatment for cutaneous T-cell lymphoma (CTCL). It acts as an agonist at the retinoid X receptor which is involved in the regulation of cellular differentiation and proliferation (Figure 6.105).
Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
The main use of pioglitazone is as a remedy for type 2 diabetes. It acts via receptor nuclear PPARγ. It attaches and forms a heterodimer with retinoid X receptor (RXR), which further leads to the alteration of the transcription of the gene and proteins related to the glucose and lipid metabolism (Application, 2013). Now it was reported that PPARγ is also involved in the neuroinflammation of the AD. Rosiglitazone is one of first PPARγ compound which was tested in the AD and entered in phase III of the clinical trials but later abandoned. Later on, pioglitazone was reported to reduce the glial cell inflammation and Aβ level in transgenic mice (Harrington et al., 2011).
Management of Vitamin A and Retinoid Side Effects
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
The most important side effect of retinoids is teratogenicity. Oral retinoids are considered as category X. Fetal malformations caused by retinoids are induced by perturbations of the neural crest cells and central nervous system (6). Two nuclear ligand-induced receptors (retinoic acid receptors and retinoid X receptors) seem to have important roles in retinoid teratogenicity by affecting downstream genes that are important in development (7). These defects, also called retinoic acid embryopathy, may lead to abnormalities of the central nervous system, face, heart, eye, and thymus (8). There is evidence that retinoids decrease the efficacy of oral contraceptives, especially progesterone-only compounds such as the minipills having only norethindrone, by inducing CYP450; therefore, additional contraception using barrier methods should be employed (9).
Retinoic acid receptor agonist as monotherapy for early-stage mycosis fungoides: does it work?
Published in Journal of Dermatological Treatment, 2019
Iris Amitay-Laish, Ofer Reiter, Hadas Prag-Naveh, Ruben Kershenovich, Emmilia Hodak
Retinoids are signaling molecules that are structurally related to vitamin A. Their biological effects are triggered through specific intracellular retinoic acid receptors (RAR) and/or retinoid X receptors (RXR) (1–3). By forming various heterodimers, they act as ligand-inducible transcription-regulatory factors and exert antiproliferative, antiangiogenic, immunomodulating and differentiation effects (3–6). Retinoids have been successfully used in the treatment of a broad range of inflammatory and neoplastic skin diseases and have proven effective in reducing cutaneous dysplasia as well as the frequency of squamous cell cancer developing in immunocompromised patients (7,8). In the treatment of cancer, retinoids are considered “biologic response modifiers” because they induce an effect without immune suppression and even frequently augment the immune response (8–14).
Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future
Published in Critical Reviews in Toxicology, 2018
Melissa A. Davidson, Donald R. Mattison, Laurent Azoulay, Daniel Krewski
PPARs undergo transactivation or transrepression through distinct mechanisms that lead to either the induction or repression of the expression of target genes (Oyekan 2011). Transactivation is DNA-dependent and binding requires dimerization with members of the retinoid X receptor (RXR) family (Willson et al. 2001). The heterodimerization between PPARs and RXR is ligand-independent, but relies on the interfaces between the ligand-binding domains and DNA-binding domains of each receptor (Chandra et al. 2008; Rochel et al. 2011). The obligate PPAR/RXR heterodimer in turn binds to PPAR responsive regulatory elements in the promoter region of target genes (Willson et al. 2001; Ajjan and Grant 2008), including those involved in adipogenesis, lipid metabolism, inflammation, and the maintenance of metabolic homeostasis (Barish et al. 2006). Activation of these genes by natural ligands or by drugs such as TZDs translates into clinically beneficial hypoglycemic and hypolipidemic effects, decreased insulin resistance, improved insulin sensitivity, and decreased inflammation (Grossman and Lessem 1997; Yki-Järvinen 2004).
Cancer prevention and treatment using combination therapy with natural compounds
Published in Expert Review of Clinical Pharmacology, 2020
vitD is the precursor of the potent steroid hormone calcitriol or 1,25-dihydroxyvitamin D3 [1,25(OH)2D], that acts in all tissues of the body by regulating the expression of hundreds of target genes. Many tissues synthesize 1,25(OH)2D from circulating 25(OH)D to regulate the expression of multiple target genes via the vitD receptor [99]. 25(OH)D is the circulating form and the best indicator of vitD status [100]. All genomic actions of active vitD are mediated by the vitD receptor, which functions as a transcription factor and as a member of the steroid hormone nuclear receptor family [101]. The mechanism of action involves direct binding of the 1,25(OH)2D/retinoic X receptor heterodimeric complex to specific DNA sequences [102].