Attenuated Tumor Aggressiveness in Hepatocellular Carcinoma by Sorafenib and Metformin Co-treatment: A Mechanism Targeting GLUT-3 and EMT Pathways

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Tekin Ç., Yıldız T. N., Erçelik M., Tunca B.

XI. Multidisciplinary Cancer Research Congress , İstanbul, Türkiye, 2 - 05 Temmuz 2026, ss.1-10, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: İstanbul
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.1-10
  • Bursa Uludağ Üniversitesi Adresli: Evet

Özet

Introduction and Aim: Hepatocellular carcinoma (HCC) is an aggressive cancer with high mortality. The long-term efficacy of standard sorafenib treatment is limited by drug resistance. Overexpression of Glucose Transporter 3 (GLUT-3), which fuels tumor energy demands, accelerates progression and metastasis. This study aims to evaluate whether combining sorafenib with metformin, which suppresses GLUT-3 expression, attenuates tumor aggressiveness in HepG2 HCC cells.

Materials and Methods: The effects of metformin (2.5–5 mM) and sorafenib on HepG2 cell proliferation were evaluated using an MTT assay to determine sorafenib's IC50. Potential drug interactions between sorafenib and metformin were calculated using the ZIP-synergy-model in SynergyFinder software. GLUT-3 and CDH2 (Epithelial-Mesenchymal Transition; EMT-marker) gene expressions were quantified by RT-qPCR. Invasion capacity was assessed via wound-healing assay and effects on 3D tumor spheroids.

Results: According to the findings, cell viability was 51.9% and 51.41% in metformin monotherapy at concentrations of 2.5 mM and 5 mM, respectively, while the IC50 of sorafenib was 7.76 µM (p<0.0001). The sorafenib+metformin combination showed an additive effect (ZIP-synergy score: -8.1). The metformin+sorafenib combination reduced GLUT-3 gene expression by 4.9-fold (p<0.0237) and CDH2 expression by 5.4-fold (p<0.004) compared to the control group. While sorafenib treatment alone did not significantly affect wound patency compared to control (p>0.05), metformin and combination therapy maintained wound patency at 92.51% and 93.82%, respectively, and statistically significantly suppressed invasion capacity compared to control (p<0.0001). Furthermore, the metformin+sorafenib combination significantly reduced 3D-tumor size (p<0.0001).

Discussion: Combining metformin and sorafenib suppresses tumor aggressiveness by simultaneously targeting glucose metabolism and EMT pathways. By inhibiting in vitro migration and reducing 3D-spheroid volume, this dual approach offers a promising therapeutic strategy to overcome resistance mechanisms associated with current monotherapies.

Acknowledgement: We thank TÜBİTAK (Project No: 1919B012327853) and Bursa Uludağ University Scientific Research Projects (Project No: TLO-2025-2163) for their financial contribution to this research.