Inhibitors of aldehyde dehydrogenases of the 1A subfamily as putative anticancer agents : Kinetic characterization and effect on human cancer cells
Jiménez, Rafael (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pequerul, Raquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Amor Minguez, Adrián (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Lorenzo Rivera, Julia (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Metwally, Kamel (Zagazig University. Department of Medicinal Chemistry)
Avilés, Francesc X (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2019
Descripció:	8 pàg.
Resum:	Aldehyde dehydrogenases (ALDHs) are enzymes catalyzing the NAD(P)+-dependent oxidation of aldehydes to their corresponding carboxylic acids. High ALDH activity has been related to some important features of cancer stem cells. ALDH1A enzymes, involved in the retinoic acid signaling pathway, are promising drug targets for cancer therapy, and the design of selective ALDH1A inhibitors has a growing pharmacological interest. In the present work, two already known compounds (DEAB and WIN 18,446) and novel thiazolidinedione and pyrimido quinoline acetic acid derivatives (compounds 5a and 64, formerly described as aldo-keto reductase inhibitors) were tested as inhibitors of the ALDH1A enzymes (namely, ALDH1A1, ALDH1A2 and ALDH1A3) as a first step to develop some potential drugs for cancer therapy. The inhibitory capacity of these compounds against the ALDH1A activity was characterized in vitro by using purified recombinant proteins. The IC50 values of each compound were determined indicating that the most potent inhibitors against ALDH1A1, ALDH1A2 and ALDH1A3 were DEAB, WIN 18,446 and compound 64, respectively. Type of inhibition and Ki values were determined for DEAB against ALDH1A1 (competitive, Ki = 0. 13 μM) and compound 64 against ALDH1A3 (non-competitive, Ki = 1. 77 μM). The effect of these inhibitors on A549 human lung cancer cell viability was assessed, being compound 64 the only inhibitor showing an important reduction of cell survival. We also tested the effect of the ALDH substrate, retinaldehyde, which was cytotoxic above 10 μM. This toxicity was enhanced in the presence of DEAB. Both DEAB and compound 64 were able to inhibit the ALDH1A activity in A549 cells. The current work suggests that, by blocking ALDH activity, drug inactivation may be avoided. Thus these results may be relevant to design novel combination therapies to fight cancer cell chemoresistance, using both enzyme inhibitors and chemotherapeutic agents.
Ajuts:	Agencia Estatal de Investigación BFU2011-24176 Agencia Estatal de Investigación BIO2016-78057
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	Aldehyde dehydrogenase ; Cancer ; Cancer stem cell ; Enzyme inhibitor ; Retinaldehyde ; Retinoic acid ; Humans ; Structure-Activity Relationship ; Cell Survival/drug effects ; Aldehyde Dehydrogenase 1 ; Aldehyde Oxidoreductases/antagonists & inhibitors ; Antineoplastic Agents/chemical synthesis ; Dose-Response Relationship, Drug ; Retinal Dehydrogenase/antagonists & inhibitors ; Molecular Structure ; Aldehyde Dehydrogenase/antagonists & inhibitors ; Cell Proliferation/drug effects ; Kinetics ; Tumor Cells, Cultured ; Enzyme Inhibitors/chemical synthesis ; Drug Screening Assays, Antitumor ; SDG 3 - Good Health and Well-being
Publicat a:	Chemico-Biological Interactions, Vol. 306 (2019) , p. 123-130, ISSN 1872-7786

DOI: 10.1016/j.cbi.2019.04.004
PMID: 30958995

34 p, 1.3 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Biotecnologia i de Biomedicina (IBB)
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