Researchers discover that Metformin reduces the anti-tumour effect of Linsitinib in the treatment of ovarian cancer

Authors and Affiliations:

Diana Luísa Almeida-Nunes ^1,2,3, João P. N. Silva ⁴, Mariana Nunes ^3,5, Patrícia M. A. Silva ^1,4,6, Ricardo Silvestre ^7,8, Ricardo Jorge Dinis-Oliveira ^1,6,9,10, Hassan Bousbaa ⁴ and Sara Ricardo ^1,2,3,4,

¹ Associate Laboratory i4HB—Institute for Health and Bioeconomy, University Institute of Health Sciences—CESPU, 4585-116 Gandra, Portugal.

² UCIBIO—Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal

³ Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal.

⁴ UNIPRO—Oral Pathology and Rehabilitation Research Unit, Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Rua Central de Gandra 1317, 4585-116 Gandra, Portugal.

⁵ School of Medicine and Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal.

⁶ UCIBIO—Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal

⁷ Life and Health Sciences Research Institute (ICVS), School of Medicine from University of Minho, 4710-057 Braga, Portugal.

⁸ ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal.

⁹ Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine from University of Porto (FMUP), 4050-319 Porto, Portugal.

¹⁰ FOREN—Forensic Science Experts, 1400-136 Lisboa, Portugal.

Abstract:

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 was 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’s or Šídák’s 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, such as the combination with standard chemotherapy in OC (carboplatin and paclitaxel).

Journal: International Journal of Molecular Sciences

Link: https://doi.org/10.3390/ijms252211935