Metabolic targeting with SGLT2 inhibitors differentially modulates cardiotoxicity and antitumor activity during HER2-targeted breast cancer therapy
N Maurea, M Barbato, R Arianna, I Santagata, A Paccone, M Berretta, M L Canale, S Oliva, C Cadeddu, D Gabrielli, F Maurea, M Scherillo, G Novo, D Di Lisi, V QuagliarielloAbstract
Background
Anthracycline- and HER2-directed therapies remain a cornerstone in the management of HER2-positive breast cancer but are frequently complicated by clinically relevant cardiotoxicity, representing a major challenge in contemporary cardio-oncology. Metabolic dysregulation and oxidative stress are increasingly recognised as shared drivers of both chemotherapy-induced myocardial injury and tumour cell survival. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have demonstrated robust cardiovascular benefit across multiple cardiometabolic conditions and have recently emerged as potential modulators of tumour metabolism. Whether SGLT2 inhibition can simultaneously preserve cardiomyocyte integrity while enhancing antitumor efficacy during HER2-targeted chemotherapy remains insufficiently defined.
Methods
Human induced pluripotent stem cell–derived cardiomyocytes and HER2-positive breast cancer cell lines (BT-474, SKBR3) were exposed to combined doxorubicin and trastuzumab, in the presence or absence of the SGLT2 inhibitors canagliflozin or dapagliflozin. Cell viability, apoptosis, oxidative stress, mitochondrial membrane potential, and inflammatory signalling were assessed using complementary biochemical and imaging approaches. Key cardioprotective and metabolic pathways (AMPK–SIRT1–Nrf2 axis) were interrogated in cardiomyocytes, while glucose transporter expression and metabolic stress responses were evaluated in tumour cells.
Results
SGLT2 inhibition exerted a context-dependent dual effect. In HER2-positive tumour cells, both canagliflozin and dapagliflozin significantly potentiated doxorubicin–trastuzumab–induced cytotoxicity, with increased apoptotic activity and suppression of glucose transporter–mediated metabolic adaptation. Conversely, in human cardiomyocytes exposed to the same chemotherapeutic stress, SGLT2 inhibitors preserved cellular viability, attenuated reactive oxygen species accumulation, stabilised mitochondrial membrane potential, and markedly reduced inflammatory cytokine release and NLRP3 inflammasome activation. Mechanistically, cardioprotection was associated with activation of AMPK-driven antioxidant and cytoprotective programmes, whereas enhanced antitumor efficacy correlated with metabolic stress induction in cancer cells. Notably, canagliflozin displayed stronger antineoplastic synergy, while dapagliflozin conferred more pronounced cardiomyocyte protection.
Conclusions
These findings identify metabolic modulation via SGLT2 inhibition as a promising strategy to dissociate antitumor efficacy from cardiotoxic liability during HER2-targeted breast cancer therapy. By exerting divergent effects on tumour cells and cardiomyocytes, SGLT2 inhibitors may offer a novel therapeutic avenue in cardio-oncology, supporting cardiovascular safety without compromising—and potentially enhancing—oncological outcomes.