Drug library screening reveals synergistic solifenacin-GLUT1 co-targeting to modulate metabolic reprogramming and epithelial-mesenchymal transition in colorectal cancer
R3FINE, İstanbul, Türkiye, 11 - 14 Haziran 2026, ss.28, (Özet Bildiri)
- Yayın Türü: Bildiri / Özet Bildiri
- Doi Numarası: 10.58847/ap.2602
- Basıldığı Şehir: İstanbul
- Basıldığı Ülke: Türkiye
- Sayfa Sayıları: ss.28
- Bursa Uludağ Üniversitesi Adresli: Evet
Özet
Colorectal cancer remains a major global health burden, particularly in metastatic disease where survival outcomes are poor. The limited efficacy and systemic toxicity of current chemotherapeutic strategies underscore the need for innovative therapeutic approaches [1]. Targeting both metabolic reprogramming through glucose transporter 1 (GLUT1) and epithelial-mesenchymal transition (EMT), a key driver of tumor aggressiveness and therapy resistance, may provide a complementary and effective therapeutic approach [2,3]. To identify novel combinatorial therapeutic strategies targeting cancer metabolism, a drug repurposing approach was employed using an FDA-approved drug library screened in combination with a GLUT1 inhibitor in human colorectal carcinoma HCT-116 cells. This systematic combinatorial screening strategy enabled the identification of compounds capable of enhancing the metabolic vulnerability induced by GLUT1 inhibition. Among the screened compounds, solifenacin, a selective antimuscarinic agent clinically approved for the treatment of overactive bladder [4], demonstrated the highest synergistic interaction with GLUT1 inhibition. To determine the optimal combination dose, sulforhodamine B assays were performed using multiple concentrations of solifenacin and the GLUT1 inhibitor. Drug interaction analyses were conducted using SynergyFinder software based on the Zero Interaction Potency, Bliss independence, Highest Single Agent models. The dose exhibiting the strongest synergistic effect across these models was selected for subsequent experiments and further validated using a CellTiter-Glo luminescence-based viability assay. Following dose confirmation, colony formation and three-dimensional spheroid assays were conducted to evaluate functional alterations. To assess the regulatory impact of the combination therapy on tumor aggressiveness, EMT was induced using transforming growth factor beta 1. EMT-associated markers were analyzed at messenger ribonucleic acid and protein levels using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, key regulators of apoptosis, necroptosis, ferroptosis, and autophagy were examined to elucidate the predominant cell death mechanisms involved. As a result, combination exerts a pronounced cytotoxic and antiproliferative effect compared to single treatments, demonstrating strong synergistic interaction. Furthermore, the combined treatment was found to suppress EMT-associated markers and enhance activation of programmed cell death pathways. These findings suggest that repurposing solifenacin in combination with metabolic targeting of GLUT1 may provide a novel and innovative therapeutic strategy for colorectal cancer management.