In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor

[EN] The epidermal growth factor receptors EGFR and HER2 are the main targets for tyrosine kinase inhibitors (TKIs). The quinazoline derivative lapatinib (LAP) is used since 2007 as dual TKI in the treatment of metastatic breast cancer and currently, it is used as an oral anticancer drug for the treatment of solid tumors such as breast and lung cancer. Although hepatotoxicity is its main side effect, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors display a considerable phototoxic potential and that afloqualone, a quinazoline-marketed drug, causes photodermatosis. Metabolic bioactivation of LAP by CYP3A4 and CYP3A5 leads to chemically reactiveN-dealkylated (N-LAP) andO-dealkylated (O-LAP) derivatives. In this context, the aim of the present work is to explore whether LAP and itsN- andO-dealkylated metabolites can induce photosensitivity disorders by evaluating their photo(geno)toxicity through in vitro studies, including cell viability as well as photosensitized protein and DNA damage. As a matter of fact, our work has demonstrated that not only LAP, but also its metaboliteN-LAP have a clear photosensitizing potential. They are both phototoxic and photogenotoxic to cells, as revealed by the 3T3 NRU assay and the comet assay, respectively. By contrast, theO-LAP does not display relevant photobiological properties. Remarkably, the parent drug LAP shows the highest activity in membrane phototoxicity and protein oxidation, whereasN-LAP is associated with the highest photogenotoxicity, through oxidation of purine bases, as revealed by detection of 8-Oxo-dG.This study was funded by the Carlos III Institute (ISCIII) of Health (Grants: PI16/01877, CPII16/00052, ARADyAL RD16/0006/0030) co-funded by European Regional Development Fund, the Spanish Government (RYC-2015-17737, CTQ2017-89416-R,) and Generalitat Valenciana (Prometeo/2017/075). We would also like to thank IIS La Fe Microscopy Unit for technical assistance.García-Laínez, G.; Vayá Pérez, I.; Marín, MP.; Miranda Alonso, MÁ.; Andreu Ros, MI. (2021). In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor. Archives of Toxicology. 95(1):169-178. https://doi.org/10.1007/s00204-020-02880-6S16917895

Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA

[EN] In this work, the attention is focused on UVA-photosensitized reactions triggered by a DNA chromophore-containing lesion, namely 5-formyluracil. This is a major oxidatively generated lesion that exhibits an enhanced light absorption in the UVB-UVA region. The mechanistic study combining photochemical and photobiological techniques shows that irradiation of S-formyluracil leads to a triplet excited state capable of sensitizing formation of cyclobutane pyrimidine dimers in DNA via a triplet-triplet energy transfer. This demonstrates for the first time that oxidatively generated DNA damage can behave as an intrinsic sensitizer and result in an important extension of the active fraction of the solar spectrum with photocarcinogenic potential. Overall, this raises the question of an aggravated photomutagenicity of the 5-formyluracil lesion.The present work was supported by Spanish Government (CTQ2015-70164-P, Severo Ochoa program/SEV-2012-0267, BES-2013-066566, CSIC 2016801007), Instituto de Salud Carlos III (RD16/0006/0030, FIS PI16/01877), Generalitat Valenciana (Prometeo/2017/075).Aparici-Espert, MI.; García-Laínez, G.; Andreu Ros, MI.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2018). Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA. ACS Chemical Biology. 13(3):542-547. https://doi.org/10.1021/acschembio.7b01097S54254713

Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles

[EN] Acute inflammation is a protective response of the body to harmful stimuli, such as pathogens or damaged cells. However, dysregulated inflammation can cause secondary damage and could thus contribute to the pathophysiology of many diseases. Inflammasomes, the macromolecular complexes responsible for caspase-1 activation, have emerged as key regulators of immune and inflammatory responses. Therefore, modulation of inflammasome activity has become an important therapeutic approach. Here we describe the design of a smart nanodevice that takes advantage of the passive targeting of nanoparticles to macrophages and enhances the therapeutic effect of caspase-1 inhibitor VX-765 in vivo. The functional hybrid systems consisted of MCM-41-based nanoparticles loaded with anti-inflammatory drug VX-765 (S2-P) and capped with poly-L-lysine, which acts as a molecular gate. S2-P activity has been evaluated in cellular and in vivo models of inflammation. The results indicated the potential advantage of using nanodevices to treat inflammatory diseases. (C) 2017 Elsevier B.V. All rights reserved.The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1-R and SAF2014-52614-R (MINECO/FEDER)) and the Generalitat Valencia (Projects PROMETEOII/2014/061 and PROMETEOII/2014/047) for support. A.G-F. is grateful to the Spanish government for an FPU grant.García-Fernández, A.; García-Laínez, G.; Ferrandiz Manglano, ML.; Aznar, E.; Sancenón Galarza, F.; Alcaraz, MJ.; Murguía, JR.... (2017). Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. Journal of Controlled Release. 248:60-70. https://doi.org/10.1016/j.jconrel.2017.01.002S607024

Accounting and Business Economics in Spain

Economia de la Empresa (Business Economics) emerged in Spain as a distinct academic discipline in the second half of the twentieth century. In its early years, Business Economics shared common influences with Accounting, particularly ideas and theories acquired from the translation of Italian and German works on Economia Aziendale and Betriebswirtschaftslehre. However, partly because of the institutional structure of Spanish universities, the two disciplines moved apart. During the Franco regime, Spanish accounting research was quite isolated, and with the return of democracy and the move towards greater European involvement much research was devoted to issues of financial accounting harmonization and standardization. This normative research was of little interest to Business Economics researchers, who were developing analytical approaches grounded in economic theory. More recently, academics working in the two disciplines have drawn on a wider range of theoretical approaches, from empirical studies to behavioural and organizational theory and institutional economics based on agency theory and transaction cost analysis. At present, the disciplines 'walk separately down the same road', but the new generation of researchers has the opportunity to bring Accounting and Business Economics closer together from an intellectual and scientific point of view.