Cellular damage photosensitized by dasatinib, radical-mediated mechanisms and photoprotection in reconstructed epidermis.

Autor: El Ouardi M; Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera S/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari I Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain., Tamarit L; Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera S/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari I Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain., Vayá I; Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera S/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari I Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain., Miranda MA; Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera S/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari I Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain. Electronic address: mmiranda@qim.upv.es., Andreu I; Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera S/n, 46022, Valencia, Spain; Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari I Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain. Electronic address: iandreur@qim.upv.es.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2024 Nov 20; Vol. 225, pp. 24-34. Date of Electronic Publication: 2024 Sep 21.
DOI: 10.1016/j.freeradbiomed.2024.09.027
Abstrakt: Dasatinib (DAS) is an anticancer drug employed in the treatment of certain hematological malignancies. Although DAS has been mainly developed for oral administration, it has recently garnered attention for its possible topical application. The use of topical drugs can cause photosensitivity, which is not listed as an adverse reaction for DAS. Since DAS absorbs UVA, it could potentially induce photosensitivity reactions and lead to oxidative damage to cellular targets. This study aims to investigate whether DAS exhibits phototoxic reactions on primary cellular targets in both solution and artificial skin, mimicking topical drug administration. It also examines the potential generation of highly reactive intermediates like organic radicals and ROS, which could trigger photosensitivity reactions. Upon DAS irradiation in the UVA region, the first transient species detected was the diradicaloid triplet excited state ( 3 DAS∗) with an absorption maximum of around 490 nm, which was quenched by oxygen to produce singlet oxygen. Quenching experiments with linoleic acid and 3-methylindole indicated that radical-mediated (Type I) photosensitized damage to lipids and proteins is possible. However, the lack of triplet quenching with guanosine suggests that the Type II mechanism also plays a role in the photooxidation of biomolecules. Accordingly, the neutral red uptake phototoxicity test (photoirritation factor of 5) and the comet assay, revealed that this drug is photo(geno)toxic to cells. Moreover, investigations on lipid photoperoxidation, and protein and DNA photooxidation strongly support that different cellular compartments are potential targets for DAS-induced phototoxicity. Regarding its potential application in topical dermatological formulations, an O/W emulsion of DAS was prepared and tested in reconstructed human epidermis, and a significant phototoxicity was also demonstrated. Fortunately, this undesired side effect disappeared upon formulation of DAS along with a sunscreen. Thus, for topical treatments, the photosensitivity reactions induced by DAS can be prevented by using formulations including appropriate UVA filters.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Inmaculada Andreu reports financial support, article publishing charges, and equipment, drugs, or supplies were provided by Spanish Ministry of Science and Innovation. Ignacio Vaya reports financial support and equipment, drugs, or supplies were provided by Generalitat Valenciana. Consellería de innovación, universidades, ciencia y sociedad digital. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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