Dapagliflozin protected human cardiomyocytes from alpelisib- and fulvestrant-induced oxidative injury under hyperglycemic conditions by restoring redox and mitochondrial homeostasis.
Does dapagliflozin prevent alpelisib- and fulvestrant-induced cardiomyocyte injury under hyperglycemic conditions in human iPSC-derived cardiomyocytes?
Dapagliflozin directly protects human cardiomyocytes from hyperglycemia-driven, PI3Kα inhibitor-associated oxidative injury, providing a mechanistic rationale for repurposing SGLT2 inhibitors as cardio-metabolic protectants in oncology.
1091 Background: Activating PIK3CA mutations occur in approximately 40% of hormone receptor–positive (HR+)/HER2-negative breast cancers and drive resistance to endocrine therapy. The PI3Kα-selective inhibitor alpelisib combined with fulvestrant significantly improves progression-free survival, as demonstrated in the SOLAR-1 trial, but its clinical benefit is limited by frequent treatment-induced hyperglycemia. Beyond metabolic toxicity, hyperglycemia promotes oxidative stress, inflammation, and mitochondrial dysfunction, thereby increasing cardiovascular vulnerability and potentially reactivating oncogenic PI3K/AKT signaling through compensatory hyperinsulinemia. Retrospective clinical evidence suggests that sodium–glucose cotransporter-2 (SGLT2) inhibitors may mitigate these effects. We investigated the direct redox-dependent cardiotoxic effects of alpelisib and fulvestrant under hyperglycemic conditions and evaluated whether dapagliflozin confers cardioprotection in human cardiomyocytes. Methods: Human iPSC-derived cardiomyocytes were exposed to alpelisib and fulvestrant under hyperglycemic conditions (25 mM glucose) in the absence or presence of dapagliflozin. Cell viability (MTS), mitochondrial membrane potential, reactive oxygen species generation, lipid peroxidation (MDA and 4-HNE), intracellular antioxidant defenses (GSH/GSSG, SOD, catalase/GPx), inflammatory and inflammasome-related mediators (IL-1β, IL-18, IL-6, TNF-α, NLRP3, MyD88), and apoptotic signaling (caspase-3/7 activity) were quantified. Cardiac injury was assessed by high-sensitivity cardiac troponin I and T release. Transcriptomic profiling was performed to interrogate cardiometabolic and redox signaling pathways. Results: Alpelisib and fulvestrant synergistically induced a pro-oxidative and pro-inflammatory injury phenotype characterized by mitochondrial depolarization, increased ROS and lipid peroxidation, depletion of antioxidant defenses, activation of the NLRP3/IL-1 axis, and caspase-dependent apoptosis. Dapagliflozin markedly restored redox homeostasis, preserved mitochondrial integrity, suppressed inflammasome and cytokine signaling, and reduced troponin release, indicating robust cardioprotection. Transcriptomic analysis confirmed coordinated downregulation of oxidative stress, inflammatory, and insulin-stress pathways. Conclusions: Dapagliflozin directly protects human cardiomyocytes from hyperglycemia-driven, PI3Kα inhibitor–associated oxidative injury by restoring redox and mitochondrial homeostasis. These findings provide a strong mechanistic rationale for repurposing SGLT2 inhibitors as dual cardio-metabolic protectants in precision oncology.
Quagliariello et al. (Wed,) conducted a other in Cardiomyocyte injury induced by alpelisib and fulvestrant under hyperglycemic conditions. Dapagliflozin vs. Absence of dapagliflozin was evaluated on Cell viability, mitochondrial membrane potential, ROS generation, lipid peroxidation, antioxidant defenses, inflammatory mediators, apoptotic signaling, and cardiac troponin release. Dapagliflozin protected human cardiomyocytes from alpelisib- and fulvestrant-induced oxidative injury under hyperglycemic conditions by restoring redox and mitochondrial homeostasis.