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Trifarotene: a Current Review and Perspectives in Dermatology

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Trifarotene: a Current Review and Perspectives in Dermatology biomedicines Review Trifarotene: A Current Review and Perspectives in Dermatology Terenzio Cosio 1,† , Monia Di Prete 2,† , Roberta Gaziano 3 , Caterina Lanna 1, Augusto Orlandi 2 , Paolo Di Francesco 3, Luca Bianchi 1 and Elena Campione 1,* 1 Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; [email protected] (T.C.); [email protected] (C.L.); [email protected] (L.B.) 2 Anatomic Pathology Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; [email protected] (M.D.P.); [email protected] (A.O.) 3 Microbiology Section, Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; [email protected] (R.G.); [email protected] (P.D.F.) * Correspondence: [email protected] † Terenzio Cosio and Monia Di Prete are equal contributors and co-first Authors. Abstract: Retinoids have numerous applications in inflammatory, dyskeratotic, and oncohematology diseases. Retinoids have now reached the fourth generation, progressively reducing toxicity whilst increasing their efficacy. Trifarotene is a new fourth-generation retinoid with a selective action on RAR-γ. In this review, we reported the trials—both concluded and in progress—including the use of trifarotene in dermatological diseases. Studies were identified by searching electronic databases (MEDLINE, EMBASE, PubMed, Cochrane, Trials.gov) from 2012 to today and reference lists of respective articles. Only articles published in English language were included. Randomized trials evaluating trifarotene tolerability, safety, and efficacy in congenital ichthyosis and acne have demonstrated great results and mild side effects, leading to the approval by the FDA of trifarotene Citation: Cosio, T.; Di Prete, M.; for the treatment of lamellar ichthyosis in 2014, and of acne vulgaris in October 2019. No high-quality Gaziano, R.; Lanna, C.; Orlandi, A.; randomized clinical trials have evaluated the treatment of primary cutaneous lymphomas with Di Francesco, P.; Bianchi, L.; Campione, E. Trifarotene: A Current trifarotene. Finally, we are hypothesizing future perspectives in the treatment of non-melanoma skin Review and Perspectives in cancers, fungal infections, photoaging, and hand-foot skin reactions with trifarotene. Dermatology. Biomedicines 2021, 9, 237. https://doi.org/10.3390/ Keywords: acne; congenital ichthyosis; T cell lymphoma; RAR-γ agonist; retinoid; trifarotene biomedicines9030237 Academic Editor: Ubaldo Armato 1. Introduction Received: 30 December 2020 Vitamin A (or retinol, a diterpene), a cardinal micronutrient in human metabolism, Accepted: 18 February 2021 is a lipophilic molecule composed by isoprene units. As an isoprenoid, it is characterized Published: 26 February 2021 by a hydrocarbon chain containing an ending hydroxyl. The term “retinoid” concerns both natural and synthetic analogues of vitamin A. In synthetic analogues, such as etreti- Publisher’s Note: MDPI stays neutral nate, acitretin, or tazarotene, a benzene ring substitutes the cyclohexane. According to with regard to jurisdictional claims in the International Union of Pure and Applied Chemistry and the International Union of published maps and institutional affil- Biochemistry and Molecular Biology, retinoids are characterized by four isoprene units iations. with a head-to-tail structure [1]. It is known that vitamin A and its synthetic analogues have a crucial role in modulating some skin functions; in particular, they regulate epidermal keratinization, differentiation, maturation, and proliferation [2]. Due to all these effects, retinoids are largely used in Copyright: © 2021 by the authors. dermato-oncology, both in treatment and chemo-prevention (non-melanoma skin cancers, Licensee MDPI, Basel, Switzerland. primary cutaneous T-cell lymphomas), and even in the treatment of cutaneous inflamma- This article is an open access article tory diseases (acne vulgaris, rosacea, melasma, post-inflammatory hyperpigmentation, distributed under the terms and mycosis) and hyperproliferative conditions (ichtyosis, psoriasis, pityriasis rubra pilaris) [2]. conditions of the Creative Commons Moreover, they play a central role in protecting the skin from free radicals damage, as Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ shown by their use also in photoaging. The aim of this review is to highlight the current 4.0/). clinical application (Figure1) of trifarotene and future perspectives in dermatology. Biomedicines 2021, 9, 237. https://doi.org/10.3390/biomedicines9030237 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 17 perpigmentation, mycosis) and hyperproliferative conditions (ichtyosis, psoriasis, pity- riasis rubra pilaris) [2]. Moreover, they play a central role in protecting the skin from free Biomedicines 2021, 9, 237 radicals damage, as shown by their use also in photoaging. The aim of this review2 is of 16to highlight the current clinical application (Figure 1) of trifarotene and future perspectives in dermatology. Figure 1.1. GraphicGraphic abstract abstract representing representing the the current current applications applications of trifaroteneof trifarotene in dermatological in dermatological clinical clinical trials trials and molecular and mo- lecular pathways. In the left section, the action of trifarotene in acne is reported. It performs both immunoregulato- pathways. In the left section, the action of trifarotene in acne is reported. It performs both immunoregulatory—leading to ry—leading to an increase in the expression of transforming growth factor-β and interleukin-4—and keratoplastic func- an increase in the expression of transforming growth factor-β and interleukin-4—and keratoplastic functions, increasing tions, increasing the expression of keratins K1, K5, K10, K14, and K16. Moreover, it seems that trifarotene, like other ret- theinoids, expression may have of keratinsa role in K1, modulating K5, K10, K14,skin andmicrobiota. K16. Moreover, Finally, trifarotene it seems that weakens trifarotene, hemidesmosomes, like other retinoids, interfering may havewith acell role adhesion. in modulating The migration skin microbiota. of keratinocytes, Finally, trifarotenecaused by weakensthe drug, hemidesmosomes,mediates its comedolytic interfering property. with cellThe adhesion.importance The of migrationtrifarotene of in keratinocytes, lamellar ichthyosis caused has by thebeen drug, reported mediates in the its central comedolytic section. property. Trifarotene, The importance by means of trifaroteneRAR-γ, causes in lamellar an in- ichthyosiscreased expression has been of reported transglutaminase in the central 1, promoting section. Trifarotene, keratinocyte by cohesion. means of RAR-The rationaleγ, causes for an the increased use of expressiontrifarotene ofin transglutaminasecutaneous T cell 1,lymphomas promoting has keratinocyte been reported cohesion. in the The right rationale section. for theIt seems use of to trifarotene promote inapoptosis cutaneous and T celldifferentiation, lymphomas hasupregulating been reported caspase in thes 3 rightand 8, section. p21 and It seemsp27. to promote apoptosis and differentiation, upregulating caspases 3 and 8, p21 and p27. 2. Mechanism of Action of Vitamin A and Its Analogues 2. MechanismStimulated of by Action Retinoic of VitaminAcid 6 (STRA6), A and Its the Analogues cell surface receptor mediates the uptake of vitaminStimulated A from by plasma Retinoic [3]. Acid Intracellular 6 (STRA6), bioavailability the cell surface is regulated receptor mediatesby specific the cyto- up- takeplasmic of vitaminretinol and A from cellular plasma retinoic [3]. Intracellularacid-binding bioavailabilityproteins, CRBPs is and regulated CRABPs, by specificrespec- cytoplasmictively. CRBPs retinol comprise and cellularfour isoforms, retinoic fr acid-bindingom CRBP-1 proteins,to CRBP CRBPs-4. The andfirst CRABPs, one is the respec- most tively.represented CRBPs in comprise many tissues. four isoforms,CRABPs fromcomprise CRBP-1 two to isoforms, CRBP-4. CRABP The first-1 oneand is CRABP the most-2. representedCRBPs and inCRABPs many tissues. specifically CRABPs bind comprise retinol twoand isoforms,retinoic CRABP-1acid (RA), and respectively. CRABP-2. CRBPsCRABPs and may CRABPs regulate specifically interactions bind between retinol and RA retinoic and its acid nuclear (RA), receptors, respectively. influencing CRABPs maybioavailable regulate RA interactions concentrations between [4]. RA Retinoids and its nuclearcan activate receptors, specific influencing genes expression bioavailable in- RAvolved concentrations in keratinocytes [4]. Retinoidsdifferentiation, can activate proliferation specific and genes apoptosis, expression binding involved specific in ker-nu- atinocytesclear receptors: differentiation, retinoic acid proliferation receptor (RAR) and apoptosis, and retinoid binding X receptor specific nuclear(RXR) [5]. receptors: In hu- retinoicmans, there acid are receptor three (RAR)genes andfor each retinoid receptor X receptor (RAR (RXR)-α, RAR [5].-β, In and humans, RAR- thereγ and are RXR three-α, α β γ α β γ genesRXR-β, for and each RXR receptor-γ), each (RAR- one encoding, RAR- , andfor several RAR- andisoforms RXR- [6]., RXR- RARs, take and RXR-steps as), eachhet- oneerodimers encoding with for RXRs several to activate isoforms the [6 transcriptio]. RARs taken of steps target as genes, heterodimers
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