Modulation of oxidative stress and metabolic burden in papillary thyroid cancer by SGLT2 and broad DPP inhibition.

INTRODUCTION: Papillary thyroid cancer (PTC) exhibits metabolic reprogramming consistent with the Warburg effect, characterized by enhanced glycolysis, redox imbalance and dependence on anti-apoptotic mechanisms such as XIAP stabilization. Modulating glucose handling and oxidative status with SGLT2 or broad DPP inhibition may therefore reveal vulnerabilities within this metabolic-apoptotic axis. This study assessed their effects on oxidative stress, glucose-dependent metabolic activity and XIAP distribution and apoptosis-related signaling in thyroid-derived cell models. METHODS: Two PTC lines (SCC147, MDA-T32) and a normal thyroid line (NTHY-ORI) were exposed for 48 h to an SGLT2 inhibitor (10-7 M), a broad, non-selective DPP inhibitor (iDPP) (10-6 M), or vandetanib (10-6 M), with doses selected by MTT viability profiling. Reactive oxygen species (ROS), lipid peroxidation (MDA), total antioxidative capacity (TAC), intracellular and extracellular XIAP, and glucose-normalized metabolic indices (IG, MS) were quantified. RESULTS: Metabolic profiling showed that SGLT2 inhibition markedly increased IG and MS in SCC147 and NTHY-ORI, consistent with altered glucose-dependent metabolic responses. In contrast, in MDA-T32 SGLT2 inhibition lowered IG/MS values, indicating reduced metabolic activity and a distinct metabolic phenotype. Both inhibitors modulated oxidative stress in a cell-line-dependent manner. SGLT2 inhibition reduced ROS levels in SCC147 (p < 0.01), whereas broad DPP inhibition reduced ROS in NTHY-ORI (p < 0.05), with no significant change observed following SGLT2 inhibition in this cell line. A significant decrease in MDA following iSGLT2 treatment was observed in SCC147 cells, whereas iDPP significantly reduced MDA levels in NTHY-ORI cells. No significant changes were detected in MDA-T32 cells. TAC responses were cell-line dependent. iDPP increased TAC in MDA-T32 and SCC147 cells, whereas both vandetanib and iDPP reduced TAC in NTHY-ORI cells. iSGLT2 did not significantly affect TAC. Extracellular XIAP changes were heterogeneous across cell lines, with the highest levels observed under different conditions depending on the cellular model. DISCUSSION: SGLT2 (10-7 M) and broad DPP inhibition (10-6 M) differentially modulated oxidative stress markers, glucose-associated metabolic indices and XIAP distribution in a strongly cell-line-dependent manner. SCC147 and NTHY-ORI exhibited marked changes in glucose-dependent metabolic indices following SGLT2 inhibition, whereas MDA-T32 showed lower glucose-dependent metabolic indices and a distinct metabolic phenotype. This divergence highlights distinct metabolic-redox vulnerabilities across thyroid cell types, underscoring the importance of cellular context in determining treatment response.