{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T10:35:33Z","timestamp":1773398133572,"version":"3.50.1"},"reference-count":85,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundac\u0327\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}]},{"name":"CESPU\u2014Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio CRL","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}]},{"name":"National funds","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}]},{"DOI":"10.13039\/501100001871","name":"FCT contract","doi-asserted-by":"publisher","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FCT\/MCTES and Uni\u00e3o Europeia (UE)","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}]},{"name":"CESPU","award":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"],"award-info":[{"award-number":["10.54499\/2020.00185.CEECIND\/CP1600\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ovarian cancer (OC) remains one of the leading causes of cancer-related mortality among women. Targeting the insulin-like growth factor 1 (IGF-1) signaling pathway has emerged as a promising therapeutic strategy. Linsitinib, an IGF-1 receptor (IGF-1R) inhibitor, has shown potential in disrupting this pathway. Additionally, metformin, commonly used in the treatment of type 2 diabetes, has been studied for its anti-cancer properties due to its ability to inhibit metabolic pathways that intersect with IGF-1 signaling, making it a candidate for combination therapy in cancer treatments. This study explores the anti-cancer effects of linsitinib and metformin on OVCAR3 cells by the suppression of the IGF-1 signaling pathway by siRNA-mediated IGF-1 gene silencing. The goal is to evaluate their efficacy as therapeutic agents and to emphasize the critical role of this pathway in OC cell proliferation. Cellular viability was evaluated by resazurin-based assay, and apoptosis was assessed by flux cytometry. The results of this study indicate that the combination of linsitinib and metformin exhibits an antagonistic effect (obtained by SynergyFinder 2.0 Software), reducing their anti-neoplastic efficacy in OC cell lines. Statistical analyses were performed using ordinary one-way or two-way ANOVA, followed by Tukey\u2019s or \u0160\u00edd\u00e1k\u2019s multiple comparison tests. While linsitinib shows promise as a therapeutic option for OC, further research is needed to identify agents that could synergize with it to enhance its therapeutic efficacy, like the combination with standard chemotherapy in OC (carboplatin and paclitaxel).<\/jats:p>","DOI":"10.3390\/ijms252211935","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T11:13:37Z","timestamp":1730891617000},"page":"11935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Metformin Impairs Linsitinib Anti-Tumor Effect on Ovarian Cancer Cell Lines"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4270-7701","authenticated-orcid":false,"given":"Diana Lu\u00edsa","family":"Almeida-Nunes","sequence":"first","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal"}]},{"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, 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\/0000-0002-4733-5778","authenticated-orcid":false,"given":"Mariana","family":"Nunes","sequence":"additional","affiliation":[{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0694-7321","authenticated-orcid":false,"given":"Patr\u00edcia M. A.","family":"Silva","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, 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":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"}]},{"given":"Ricardo","family":"Silvestre","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine from University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-6297","authenticated-orcid":false,"given":"Ricardo Jorge","family":"Dinis-Oliveira","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 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":"Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine from University of Porto (FMUP), 4050-319 Porto, Portugal"},{"name":"FOREN\u2014Forensic Science Experts, 1400-136 Lisboa, 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, 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\/0000-0003-4091-2226","authenticated-orcid":false,"given":"Sara","family":"Ricardo","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal"},{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), Rua Central de Gandra 1317, 4585-116 Gandra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"De Leo, A., Santini, D., Ceccarelli, C., Santandrea, G., Palicelli, A., Acquaviva, G., Chiarucci, F., Rosini, F., Ravegnini, G., and Pession, A. 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