{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T02:24:00Z","timestamp":1778552640166,"version":"3.51.4"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universit\u00e0 del Piemonte Orientale","award":["MFAG-2021 #26004"],"award-info":[{"award-number":["MFAG-2021 #26004"]}]},{"name":"Associazione Italiana di Ricerca sul Cancro","award":["MFAG-2021 #26004"],"award-info":[{"award-number":["MFAG-2021 #26004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.<\/jats:p>","DOI":"10.3390\/ijms24076689","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T02:30:15Z","timestamp":1680575415000},"page":"6689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment"],"prefix":"10.3390","volume":"24","author":[{"given":"Sara","family":"Boumya","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-7417","authenticated-orcid":false,"given":"Silvia","family":"Fallarini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Siragusa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6586-6783","authenticated-orcid":false,"given":"Giovanni","family":"Petrarolo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56100 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4804-9543","authenticated-orcid":false,"given":"Silvio","family":"Aprile","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5660-4175","authenticated-orcid":false,"given":"Valentina","family":"Audrito","sequence":"additional","affiliation":[{"name":"Department of Science and Technological Innovation, University of Piemonte Orientale, 15121 Alessandria, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Concettina","family":"La Motta","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56100 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-1729","authenticated-orcid":false,"given":"Silvia","family":"Garavaglia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Pinton","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1200\/JCO.21.01567","article-title":"New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options","volume":"40","author":"Tsao","year":"2022","journal-title":"J. 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