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

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.

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.

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.

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.