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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The retinoids are natural and synthetic derivatives of vitamin A that regulate a variety of important cellular functions. Retinol (Figure 6.106), also known as vitamin A1, is a vitamin found in many food types and used as a dietary supplement to treat and prevent vitamin A deficiency. In the body retinol is converted to retinal and then retinoic acid which acts on cell-surface receptors to control processes including cell growth and metabolism (Figure 6.105). In particular, it is a regulator of epithelial and bone tissue cell growth and differentiation, and so analogues have been developed for use in skin-related proliferative diseases such as psoriasis and bone tissue disorders. Through the activation of tumor-suppressor genes, it is also known to play a role in maintaining vision and immune function. Retinol was discovered in 1909, isolated in 1931 and first synthesized in 1947, and dietary sources rich in the molecule include dairy products, meat, and fish. All-trans-retinoic acid (RA) works by activating the Nuclear Retinoic Acid receptors (RARs), while 9-cis-retinoic acid activates the non-classical nuclear Retinoid X Receptors (RXRs) along with the RARs. Altogether, there are six genes encoding the retinoid receptors: RARa, RARb, and RARg, and RXRa, RXRb, and RXRg (Figure 6.105).
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
The effects of RA on cells are mediated by RA responsive receptors (RAR): retinoic acid receptor alpha (RARA or RAR-α), beta (RARB or RAR-β), and gamma (RARG or RAR-γ) and the peroxisome proliferator-activated receptor beta and delta (PPARB or PPAR-β and PPARD or PPAR-δ) which belong to the nuclear receptor superfamily (6). They function as RA ligand-dependent transcription factors which form heterodimers with the retinoid X receptors (RXRs), and mediate transcription by binding to DNA. Heterodimers RAR/RXR bind to cis acting RA response elements (RAREs), while PPAR/RXR heterodimers bind to peroxisome proliferator response element (PPRE) (Figure 8.1) (7–9). The precise control of RARs is necessary for the correct balance between self-renewal and differentiation of tissue stem cells. The loss, accumulation, mutations, or aberrant modifications of RARs results in oncogenic transformation with disturbance in differentiation and uncontrolled proliferation of cells (10). The targets of RA and RARs/PPAR-β/δ include many structural genes, oncogenes, transcription factors, and cytokines.
Current Recommendations for the Treatment of Psoriasis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Tazarotene is the only topical retinoid that has been shown to be effective in treating psoriasis plaques.19,20 It binds selectively to retinoic acid receptor beta and gamma. Studies have shown that tazarotene application can downregulate markers of keratinocyte proliferation and upregulate the tazarotene-induced genes TIG-1, TIG-2, and TIG-3 thought to be involved in antiproliferation.21,22 Tazarotene was shown to be as effective as fluocinonide in reducing plaque elevation in one study.23 Irritation in up to 23% of patients limits its use; it is therefore often combined with a topical corticosteroid to enhance efficacy and reduce irritation.24,25
Acute myeloid leukemia with NUP98::RARG resembling acute promyelocytic leukemia accompanying ARID1B gene mutation
Published in Hematology, 2023
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by fatal coagulation abnormalities. More than 98% of patients with APL have a promyelocytic leukemia–retinoic acid receptor alpha (PML::RARA) fusion gene caused by the chromosomal translocation t (15; 17) (q22; q21), which is sensitive to therapy with ATRA and arsenic trioxide (ATO) therapy[1,2]. However, certain AML subtypes exhibit the APL phenotype and APL-like syndromes, with X::RARs fusion genes rather than the PML–RARA fusion gene [2]. In the past few years, X::RARA has been well described, including PLZF::RARA, NPM1::RARA, and STAT5B::RARA. Furthermore, retinoic acid receptor beta(RARB) and retinoic acid receptor gamma(RARG) rearrangements have been discovered to contribute to APL-like syndromes [3]. Notably, RARB and RARG share high sequence homology with RARA[4], and unlike PML::RARA fusions, most novel X::RAR fusions are ATRA or ATO resistant. In this study, we report the case of a patient with AML with a NUP98::RARG rearrangement and review our current understanding of patients with AML harboring X::RAR fusion gene.
Genetic and molecular determinants of prostate cancer among Iranian patients: An update
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Majid Ghayour-Mobarhan, Gordon A. Ferns, Meysam Moghbeli
In addition to cell surface receptors, nuclear receptors participate in cellular transduction systems. Retinoic acid receptor beta (RARB) is a nuclear thyroid-steroid hormone receptor associated with cell growth and differentiation through binding with retinoic acid and retinoic acid response elements (RARE). Assessment of RARB and CDKN2a promoter methylation status in a subpopulation of Iranian subjects showed the prognostic value of RARB and p16 promoter hypermethylation in PCa compared with benign prostatic hyperplasia (BPH) cases. Hypermethylation of RARB and p16 was more frequent among patients with a poor prognosis compared with those with a good prognosis [55]. RARB methylation in benign prostate samples was significantly correlated with increased risk of subsequent PCa among black men [56].
Identification of key transcription factors in preeclampsia
Published in Hypertension in Pregnancy, 2019
Junhu Wang, Huijie Liu, Yunxia Guo, Chunxiao Zhou, Tingting Qi
Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. It was proposed that increased RA may contribute to preeclampsia pathogenesis by reducing sFLT1 accumulation at the maternal–fetal interface (24). Thus, it is coincidence with our finding that RA was a key factor in preeclampsia. TP53 plays a crucial role in regulating cell apoptosis by activating the expression of proapoptotic protein Bax and inhibiting antiapoptotic protein Bcl-2 and BIRC5 expressions at the transcriptional level (25,26). It is proposed that upregulation of P53 was involved in triggering cell apoptosis in cultured human umbilical vein endothelial cell (HUVECs) from preeclampsia pregnancies by regulating Bax gene, Bcl-2, and BIRC5 genes (27). Besides, an upregulation of the TP53 pathway was reported to induce the deportation of microparticles, including high levels of antiangiogenic factors, and that this might facilitate maternal systemic symptoms in preeclampsia (28).