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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).
Historical Milestones
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
In 1957, Leif Hillestad (Oslo) described three patients with acute leukaemias who had a rapid curse of illness accompanied by severe bleeding and ‘excessive’ promyelocytes in the peripheral blood. He coined the term ‘acute promyelocytic leukaemia’ (APL) to describe them. He also acknowledged that similar cases might have been described earlier by Risak (1935), Cooperberg (1955) and Pisciotta (1955). Then in 1988, Marie-Geneviéve Mattei and her colleagues, whilst working in Marseille and Strasbourg on the specificity of all-trans-retinoic acid (ATRA) treatment for APL, described the location of the retinoic acid receptor alpha (RARα) gene on the long arm of chromosome 17. The partner gene of RARA in the t(15;17) translocation was completely sequenced in 1991 by de Thé and colleagues in Paris, and Kakizuka and colleagues in La Jolla, California. The t(15;17) translocation generates a PML/RARα fusion protein which is considered to be the pathogenetic cause of APL.
Cytogenetics
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The reciprocal translocation t(15;17)(q24;q12–21) is the diagnostic hallmark of APL [220]. The t(15;17) translocation creates two chimeric genes: the PML–RARA gene is formed on the derivative 15, whereas the reciprocal RARA–PML fusion is located on the derivative 17 (Figure 6.37). PML (promyelocytic leukemia) gene possesses growth suppressor and proapoptotic activity [255,256]. RARA is a transcription factor that mediates the effect of retinoic acid. The PML–RARA plays an important role in leukemogenesis by impairing the growth suppressor and proapoptotic activities of PML. It is also important in mediating the differentiation response to the ATRA treatment [41,220,257]. The introduction of novel targeted therapies in the form of ATRA and arsenic trioxide changed the clinical course of APL over the past 25 years from one that was fatal for the majority of patients to the most curable subtype of AML. Reciprocal translocation of 17q21 is found in >95% of APL. The remaining APL cases show complex or variant translocations involving chromosome 15 or 17 and other chromosomes as well as masked (cryptic) insertions.
All-Trans Retinoic Acid Promotes M2 Macrophage Polarization in Vitro by Activating the p38MAPK/STAT6 Signaling Pathway
Published in Immunological Investigations, 2023
Ya-nan Zhu, Xiao-li Gu, Lin-yuan Wang, Ning Guan, Chen-guang Li
The polarization of M2 macrophages is a complex process with multi-factor interactions regulated by multiple intracellular signaling molecules and their pathways. It was previously demonstrated that phosphatidylinositol-3-kinase (PI3K) catalyzes the production of the second messenger phosphatidylinositol 3,4,5-tricarboxyinositol (PIP3), which then activates the downstream Akt serine/threonine kinase and promotes macrophage polarization toward M2-type macrophages (Da-Wa et al. 2021; Zhao et al. 2020; Zhou et al. 2019). ATRA was found to induce the Retinoic acid receptor alpha (RARα) to localize to the cell membrane and bind to PI3K subunits, which in turn activates the PI3K/AKT signaling pathway (Wang et al. 2021; Wei et al. 2018). Our study suggests that ATRA may also promote the polarization of M2-type macrophages by activating the PI3K/AKT signaling pathway. Blazanin et al. (2019) identified that macrophages can regulate macrophage polarization through Toll-like Receptor 4 (TLR4) activation of the TLR2/nuclear factor-κB (NF-κB) signaling pathway, and ATRA can enhance macrophage phagocytosis and reduce inflammation by blocking NF-κB signaling through inhibition of CD14/TLR4 expression (Li et al. 2021). Our study suggests that ATRA may also promote M2 macrophage polarization by blocking the TLR4/NF-κB signaling pathway. Therefore, ATRA may also exert anti-inflammatory effects by regulating macrophage polarization through other signaling pathways, and further studies are needed to reveal more mechanisms of action.
Role of oxidative stress in pathophysiology of rheumatoid arthritis: insights into NRF2-KEAP1 signalling
Published in Autoimmunity, 2021
Gurjasmine Kaur, Aman Sharma, Archana Bhatnagar
Nrf2 comprises seven functional Nrf2-ECH homologies (Neh) domains, with Neh1, 3, and 6 at C- terminus [42]. Neh1 is a CNC-bZIP domain that allows Nrf2 to heterodimerize with sMaf proteins, DNA, and other transcription partners as well as forming a nuclear complex with ubiquitin-conjugating enzyme, UbcM2. Neh2 contains two important motifs, ETGE and DLG, essential for interaction with Keap1 and a hydrophilic region of seven lysine residues necessary for Keap1-dependent Nrf2 polyubiquitination. Neh3 domain is critically required for activation of transcription, along with Neh4 and Neh5 domain, that bind to Kinase-inducible interacting domain and Cysteine/histidine-rich domain 3 of cAMP Responsive Element Binding protein (CREB)-binding protein (CBP/CREB-BP) to induce transactivation. Neh6 domain regulates Keap1-independent Nrf2 negative regulation by glycogen synthase kinase 3-β (GSK-3β) phosphorylation, creating a recognition motif for β-transducin repeat containing E3 ubiquitin-protein ligase (β-TrCP). Neh7 domain binds to the retinoic acid receptor-alpha. Recent implications demonstrated Keap1-independent Nrf2 ubiquitination during ER stress via ER-associated degradation-associated E3 ubiquitin ligase [42].
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).