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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Targeted therapies have substantially advanced cancer treatment; however, therapeutic resistance remains a major challenge, particularly in lung cancer. Polo-like kinase 1 (PLK-1), a key regulator of mitosis, is frequently overexpressed in lung tumors and has emerged as an attractive anticancer target. Although PLK-1 inhibition induces robust antitumor effects in preclinical models, its translation into clinical benefit has been limited, particularly when used as monotherapy. Previous in vitro work from our group demonstrated that combining PLK-1 inhibition with the pro-apoptotic agent Navitoclax markedly enhanced cancer cell death by reducing mitotic slippage and promoting post-mitotic apoptosis. Here, we investigated whether this combinatorial strategy translates into therapeutic benefit in vivo. Using Lewis lung carcinoma (LLC1) cells, we evaluated the effects of BI2536 (a PLK-1 inhibitor) and Navitoclax, alone or in combination, in vitro and in male C57BL\/6J mice using three lung cancer models: subcutaneous, intranasal, and intrapulmonary. The in vitro results corroborated the findings of our previous work, demonstrating synergistic effects. In the murine models, tumor progression, body weight, survival, and histopathological features were assessed to evaluate therapeutic efficacy and systemic toxicity. In the subcutaneous model, BI2536 monotherapy significantly reduced tumor volume compared with vehicle-treated controls, while Navitoclax alone and the combination therapy also produced tumor growth inhibition. In contrast, in the intranasal model, no significant differences were observed in body weight or survival among groups. Nonetheless, treatment with BI2536 alone or in combination with Navitoclax significantly reduced tumor cell proliferative activity. In the aggressive intrapulmonary (orthotopic) model, rapid disease progression and high mortality were observed across all groups. Notably, BI2536 treatment was associated with improved survival compared with Navitoclax monotherapy, whereas the combination therapy did not confer additional survival benefit. Histological analyses revealed highly proliferative tumors with pronounced cellular and nuclear atypia. Moreover, the BI2536 monotherapy group exhibited significantly greater necrosis\/apoptosis than the other treatment groups, while diffuse and focal hepatic steatosis was observed exclusively in the combination group. Together, these findings indicate that while PLK-1 inhibition exerts antitumor effects in certain in vivo contexts, the therapeutic synergy observed in vitro with Navitoclax does not consistently translate to in vivo lung cancer models. This study highlights the challenges of translating combinatorial mitotic and apoptotic targeting strategies into effective in vivo therapies and underscores the importance of model selection and tumor microenvironment in preclinical drug evaluation.<\/jats:p>","DOI":"10.3390\/ijms27167359","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:35:08Z","timestamp":1786984508000},"page":"7359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical Evaluation of Combined Polo-like Kinase 1 Inhibition and Navitoclax in Experimental Models of Lung Cancer"],"prefix":"10.3390","volume":"27","author":[{"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), 4585-116 Gandra, Portugal"},{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0508-5298","authenticated-orcid":false,"given":"Mateus","family":"Prates-Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9590-8059","authenticated-orcid":false,"given":"Daniel Augusto Barnabe","family":"Nobre","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1376-5964","authenticated-orcid":false,"given":"Mariana de Oliveira","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-1049","authenticated-orcid":false,"given":"B\u00e1rbara M.","family":"de Amorim-Santos","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4455-4286","authenticated-orcid":false,"given":"Jo\u00e3o P. N.","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), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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), 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[{"name":"i3S-Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"INEB-Institute of Biomedical Engineering, University of Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-3393","authenticated-orcid":false,"given":"Marisa","family":"Salvi","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5650-6743","authenticated-orcid":false,"given":"Geovanni Dantas","family":"Cassali","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine Maria de","family":"Souza-Fagundes","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Pres. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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), 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Carvalho-Tavares","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. 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