El Ouardi Meryem, Tamarit Lorena, Vayá Ignacio, Miranda Miguel A, Andreu Inmaculada
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.
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.
Free Radic Biol Med. 2024 Nov 20;225:24-34. doi: 10.1016/j.freeradbiomed.2024.09.027. Epub 2024 Sep 21.
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 (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.
达沙替尼（DAS）是一种用于治疗某些血液系统恶性肿瘤的抗癌药物。尽管DAS主要开发用于口服给药，但它最近因其可能的局部应用而受到关注。局部用药可能会引起光敏感性，而这并未被列为DAS的不良反应。由于DAS吸收紫外线A（UVA），它可能会引发光敏感反应并导致细胞靶点的氧化损伤。本研究旨在调查DAS在溶液和人工皮肤中对原代细胞靶点是否表现出光毒性反应，模拟局部给药情况。它还研究了是否会产生如有机自由基和活性氧（ROS）等高活性中间体，这些中间体可能引发光敏感反应。在UVA区域照射DAS时，检测到的第一个瞬态物种是吸收最大值约为490nm的双自由基三重激发态（DAS∗），它被氧气淬灭以产生单线态氧。用亚油酸和3-甲基吲哚进行的淬灭实验表明，自由基介导的（I型）对脂质和蛋白质的光致敏损伤是可能的。然而，用鸟苷进行三重态淬灭实验的结果表明，II型机制在生物分子的光氧化过程中也起作用。因此，中性红摄取光毒性试验（光刺激因子为5）和彗星试验表明，这种药物对细胞具有光（基因）毒性。此外，对脂质光过氧化以及蛋白质和DNA光氧化的研究有力地支持了不同细胞区室是DAS诱导的光毒性的潜在靶点。关于其在局部皮肤制剂中的潜在应用，制备了DAS的水包油乳液并在重建的人表皮中进行了测试，结果也显示出显著的光毒性。幸运的是，将DAS与防晒霜一起配制后，这种不良副作用消失了。因此，对于局部治疗，通过使用包含适当UVA滤光剂的制剂，可以预防DAS诱导的光敏感反应。
