Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma
Jiménez, Rafael (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Constantinescu, Andrada (Advanced BioDesign (France))
Yazir, Muhube (Advanced BioDesign (France))
Alfonso Triguero, Paula (Institut Català de Nanociència i Nanotecnologia)
Pequerul Pavón, Raquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pérez-Alea, Mileidys (Advanced BioDesign (France))
Candiota Silveira, Ana Paula (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Lorenzo Rivera, Julia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2024
Abstract:	Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40-50%.
Grants:	Agencia Estatal de Investigación PID2020-119424RB-I00 Agencia Estatal de Investigación PID2020-113058GB-I00 Agencia Estatal de Investigación PID2021-127983OB-C22 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00135 Ministerio de Sanidad y Consumo CB06/01/0010
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Aldehyde dehydrogenase ; Cancer ; Enzyme inhibition ; Glioblastoma ; Retinoic acid
Published in:	International journal of molecular sciences, Vol. 25 (October 2024) art. 11512, ISSN 1422-0067

DOI: 10.3390/ijms252111512
PMID: 39519068

26 p, 5.5 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > Catalan Institute of Nanoscience and Nanotechnology (ICN2)
Articles > Research articles
Articles > Published articles