{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T22:30:42Z","timestamp":1774477842556,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CESPU\u2014Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio under the project \u201cAntiMitoSphere_APSFCT_IINFACTS_2021\u201d to Hassan Bousbaa","award":["grant BD\/CBAS\/CESPU\/01\/2020"],"award-info":[{"award-number":["grant BD\/CBAS\/CESPU\/01\/2020"]}]},{"name":"CESPU\u2014Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio under the project \u201cAntiMitoSphere_APSFCT_IINFACTS_2021\u201d to Hassan Bousbaa","award":["grant SFRH\/BD\/116167\/2016"],"award-info":[{"award-number":["grant SFRH\/BD\/116167\/2016"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["grant BD\/CBAS\/CESPU\/01\/2020"],"award-info":[{"award-number":["grant BD\/CBAS\/CESPU\/01\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["grant SFRH\/BD\/116167\/2016"],"award-info":[{"award-number":["grant SFRH\/BD\/116167\/2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The efficacy of antimitotics is limited by slippage, whereby treated cells arrested in mitosis exit mitosis without cell division and, eventually, escape apoptosis, constituting a serious resistance mechanism to antimitotics. Strategies to overcome slippage should potentiate the cancer cell killing activity of these antimitotics. Such strategies should accelerate cell death in mitosis before slippage. Here, we undertook a mechanistic analysis to test whether the apoptosis activator Navitoclax potentiates apoptosis triggered by the antimitotic BI2536, a potent inhibitor of Polo-like kinase 1 (PLK1) with the goal of overcoming slippage. We found that cancer cells in 2D cultures treated with BI2536 alone accumulate in mitosis, but a significant fraction of arrested cells undergo slippage and survive. Remarkably, combining BI2536 with Navitoclax dramatically reduces slippage, shifting the cell fate to accelerated death in mitosis. The results are confirmed in 3D spheroids, a preclinical system that mimics in vivo tumor drug responses. Importantly, in 3D spheroids, the effect of the BI2536\/Navitoclax combination requires a lower therapeutic dosage of each drug, underlying its potential to improve the therapeutic index. Our results highlight the relevance of apoptosis potentiators to circumvent slippage associated with antimitotics. The combination of BI2536 with Navitoclax shows in vitro synergy\/additive effect, which warrants further clinical research.<\/jats:p>","DOI":"10.3390\/pharmaceutics14061209","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T00:10:33Z","timestamp":1654560633000},"page":"1209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Navitoclax Enhances the Therapeutic Effects of PLK1 Targeting on Lung Cancer Cells in 2D and 3D Culture Systems"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8804-6104","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Pinto","sequence":"first","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"},{"name":"Departamento de Fisiologia e Biof\u00edsica, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-9807","authenticated-orcid":false,"given":"Pedro","family":"Novais","sequence":"additional","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"},{"name":"Faculty of Sciences, University of Porto, Rua do Campo Alegre, s\/n, 4169-007 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Ana C.","family":"Henriques","sequence":"additional","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"}]},{"given":"Juliana","family":"Carvalho-Tavares","sequence":"additional","affiliation":[{"name":"Departamento de Fisiologia e Biof\u00edsica, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0694-7321","authenticated-orcid":false,"given":"Patr\u00edcia M. A.","family":"Silva","sequence":"additional","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"},{"name":"TOXRUN\u2014Toxicology Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-5779","authenticated-orcid":false,"given":"Hassan","family":"Bousbaa","sequence":"additional","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal"},{"name":"Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental (CIIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020. CA","volume":"70","author":"Siegel","year":"2020","journal-title":"Cancer J. Clin."},{"key":"ref_2","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., and Lewis, D.R. (2021, November 15). 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