ReviewSelective retinoids and rexinoids in cancer therapy and chemoprevention
Section snippets
Diversity and mechanisms-of-action of the retinoid receptors
The retinoid signal is mediated in target cells through RARs and RXRs, each of which comprise three isotypes designated α, β and γ as well as several isoforms generated by alternative splicing or promoter use [9]. Retinoic acid receptors and RXRs are divergent in their ligand specificity; ATRA can bind and activate only RAR receptors, with a similar affinity for all three isotypes. By contrast, 9cRA binds and activates all three RARs and RXRs, but with different affinities [10]. Retinoic acid
Why is selectivity needed for retinoid-based therapies?
The beneficial therapeutic potential of retinoids is counterbalanced by their toxicity. Taken together, studies on vitamin A deficiency (VAD) and genetic inactivation of the retinoid receptors indicate that vitamin A is essential during pre- and post-natal development, as well as in adult life, and that the retinoid receptors are responsible for mediating the physiological functions of retinoic acids derived from vitamin A. Indeed, similar abnormalities in fetal development of the respiratory
General background
Synthetic retinoids have been the subject of chemical investigation since the early 1960s. Early attempts to overcome the air-, light- and metabolic-instability of retinoic acid led to the replacement of the polyene chain in the natural vitamin with aromatic groups (Fig. 2). Discovery of the individual retinoic acid receptors spurred further successful investigations into modifications conferring binding specificity. Several reviews of retinoid structural evolution have been published 35., 36.,
Activity of selective retinoids for tumor growth inhibition
The use of RARα-selective agonists in the treatment of APL is a very attractive therapeutic approach because the underlying pathology involves oncogenic fusion proteins with the α-isotype of RAR. Accordingly, the selective RARα agonists, AM80, AM580 and BMS194753, were shown to induce differentiation of the acute promyelocytic leukemia cell lines HL60 and NB4, and this effect was reversed by the selective RARα antagonist BMS195614 18., 48.. Furthermore, AM80 successfully induced complete
Activity of rexinoids
Retinoid X receptors are promiscuous dimerization partners for a large number of nuclear hormone receptors; rexinoid ligands therefore have the potential to affect multiple signal transduction pathways. One of these ligands, the RXR agonist LGD1069 (Targretin; Fig. 5), was shown to prevent the formation and progression of primary and secondary N-nitroso-N-methylurea (NMU)-induced rat mammary carcinomas. These effects of LGD1069 were also observed in tamoxifen refractory breast tumors of the NMU
The future of selective retinoids in cancer therapy and chemoprevention
Development of the natural vitamin A derivatives, including ATRA, 9cRA and 13cRA, as oral chemotherapeutic agents has been compromised by the severe adverse toxicities they generate through regulation of multiple receptor isotypes. The generation of retinoids and rexinoids with restricted selectivity has opened new avenues for cancer therapy and chemoprevention. However, instead of a broad use, these compounds should be restricted to particular malignancies, such as the use of RARα agonists in
Acknowledgements
We are extremely grateful to Hinrich Gronemeyer and Nature Reviews for permission to use Fig. 1, originally published in [13]. We also thank Marco Gottardis for helpful discussion and support.
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2018, Bioorganic and Medicinal Chemistry LettersInterplay between estrogen and retinoid signaling in breast cancer - Current and future perspectives
2014, Cancer LettersCitation Excerpt :Despite the promising results obtained in vitro, few clinical trials were conducted to clarify the therapeutic potential of RA in breast cancer [21] and RA did not present significant activity in patients with hormone-refractory, metastatic breast cancer [22]. Moreover, retinoids are known teratogens and Vitamin A excess is toxic to several organs and tissues, including the liver, central nervous system, musculoskeletal system, internal organs, and skin [3,4]. In phase I/II studies, RA induced cheilitis, skin reactions, headache, nausea and vomiting, as well as elevations of liver enzymes and triglycerides; skin toxicities and headaches were considered to be the dose-limiting toxicity [23,24].
Effects of all-trans-retinoic acid on the permeability transition and bioenergetic functions of rat liver mitochondria in combination with endoxifen
2013, Life SciencesCitation Excerpt :All-trans-retinoic acid (RA), the most abundant natural retinoid, has been widely used in the treatment of visual and skin conditions, such as acne and psoriasis (Bushue and Wan, 2010; Tang and Gudas, 2011). RA exhibits anti-proliferative and pro-apoptotic activity, and its use has been extensively evaluated in cancer prevention and therapy (Xun et al., 2012; Zusi et al., 2002). However, the severe side effects induced by RA, including skin toxicities, teratogenic effects and elevation of serum cholesterol and triglycerides, have been a major obstacle to its clinical utilization (Lee et al., 1993; Warren and Griffiths, 2008; Zusi et al., 2002).
CRABP-II methylation: A critical determinant of retinoic acid resistance of medulloblastoma cells
2012, Molecular OncologyCitation Excerpt :The overlapped CRABP-I and CRABP-II silencing was only found in 18/58 (31.0%) of the classic, 10/40 (25%) of the anaplastic/large cell and 3/6 (50%) of the anaplastic/desmoplastic tumors (p > 0.05; Figure 7c and d). RA has been widely used in cancer chemotherapy because of its property to suppress growth and to induce differentiation and apoptosis (Meyskens and Manetta, 1995; Zusi et al., 2002; Ravandi, 2009). Several cytosolic elements can influence the biological effects of RA.
Retinoid chemistry: Synthesis and application for metabolic disease
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