A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro
Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the hig...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-01-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/13/2/356 |
_version_ | 1797409654044622848 |
---|---|
author | Edoardo L. M. Gelardi Giorgia Colombo Francesca Picarazzi Davide M. Ferraris Andrea Mangione Giovanni Petrarolo Eleonora Aronica Menico Rizzi Mattia Mori Concettina La Motta Silvia Garavaglia |
author_facet | Edoardo L. M. Gelardi Giorgia Colombo Francesca Picarazzi Davide M. Ferraris Andrea Mangione Giovanni Petrarolo Eleonora Aronica Menico Rizzi Mattia Mori Concettina La Motta Silvia Garavaglia |
author_sort | Edoardo L. M. Gelardi |
collection | DOAJ |
description | Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies. |
first_indexed | 2024-03-09T04:18:41Z |
format | Article |
id | doaj.art-2238cafff5614e27bf79b99fbee01a0d |
institution | Directory Open Access Journal |
issn | 2072-6694 |
language | English |
last_indexed | 2024-03-09T04:18:41Z |
publishDate | 2021-01-01 |
publisher | MDPI AG |
record_format | Article |
series | Cancers |
spelling | doaj.art-2238cafff5614e27bf79b99fbee01a0d2023-12-03T13:50:12ZengMDPI AGCancers2072-66942021-01-0113235610.3390/cancers13020356A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In VitroEdoardo L. M. Gelardi0Giorgia Colombo1Francesca Picarazzi2Davide M. Ferraris3Andrea Mangione4Giovanni Petrarolo5Eleonora Aronica6Menico Rizzi7Mattia Mori8Concettina La Motta9Silvia Garavaglia10Department of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyDepartment of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, 53100 Siena, ItalyDepartment of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyDepartment of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, 1105 Amsterdam, The NetherlandsDepartment of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyDipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, 53100 Siena, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmaceutical Sciences, University of Piemonte Orientale, A. Avogadro, 28100 Novara, ItalyAldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.https://www.mdpi.com/2072-6694/13/2/356aldehyde dehydrogenasescancer therapycancer stem cellstarget validationglioblastomabiochemistry |
spellingShingle | Edoardo L. M. Gelardi Giorgia Colombo Francesca Picarazzi Davide M. Ferraris Andrea Mangione Giovanni Petrarolo Eleonora Aronica Menico Rizzi Mattia Mori Concettina La Motta Silvia Garavaglia A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro Cancers aldehyde dehydrogenases cancer therapy cancer stem cells target validation glioblastoma biochemistry |
title | A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro |
title_full | A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro |
title_fullStr | A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro |
title_full_unstemmed | A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro |
title_short | A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro |
title_sort | selective competitive inhibitor of aldehyde dehydrogenase 1a3 hinders cancer cell growth invasiveness and stemness in vitro |
topic | aldehyde dehydrogenases cancer therapy cancer stem cells target validation glioblastoma biochemistry |
url | https://www.mdpi.com/2072-6694/13/2/356 |
work_keys_str_mv | AT edoardolmgelardi aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT giorgiacolombo aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT francescapicarazzi aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT davidemferraris aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT andreamangione aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT giovannipetrarolo aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT eleonoraaronica aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT menicorizzi aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT mattiamori aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT concettinalamotta aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT silviagaravaglia aselectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT edoardolmgelardi selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT giorgiacolombo selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT francescapicarazzi selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT davidemferraris selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT andreamangione selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT giovannipetrarolo selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT eleonoraaronica selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT menicorizzi selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT mattiamori selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT concettinalamotta selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro AT silviagaravaglia selectivecompetitiveinhibitorofaldehydedehydrogenase1a3hinderscancercellgrowthinvasivenessandstemnessinvitro |