Key result
SGLT2 inhibition attenuates doxorubicin-vincristine cardiotoxicity in human cardiomyocytes without compromising anti-tumor efficacy.
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Why the study?
Whether the combination of doxorubicin and vincristine exacerbates cardiotoxicity and the underlying mechanisms remain unclear.
Does SGLT2 inhibition attenuate doxorubicin and vincristine-induced cardiotoxicity in human iPSC-derived cardiomyocytes without compromising anti-tumor efficacy?
Does SGLT2 inhibition attenuate doxorubicin and vincristine-induced cardiotoxicity in human iPSC-derived cardiomyocytes without compromising anti-tumor efficacy?
SGLT2 inhibition can partially mitigate the exacerbated cardiotoxicity caused by combined doxorubicin and vincristine treatment in human cardiomyocytes while preserving anti-tumor efficacy.
BACKGROUND Doxorubicin is a well-known cardiotoxic chemotherapeutic agent. Whether its combination with vincristine exacerbates cardiotoxicity and the underlying mechanisms remains unclear. METHODS Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) were treated with doxorubicin, vincristine, or both. Cellular apoptosis, signaling, and mitochondrial function were assessed. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and pharmacological modulators were used to test protective effects, and lymphoma cells were used to evaluate potential impacts on chemotherapeutic efficacy. RESULTS Vincristine potentiated doxorubicin-induced apoptosis in iPSC-CMs, while having minimal effect alone. Combination treatment was accompanied by microtubule disruption, endoplasmic reticulum stress responses, and JNK phosphorylation, along with mitochondrial morphological alterations. SGLT2 inhibition partially attenuated apoptotic signaling under combination treatment conditions without reducing the cytotoxic effects of doxorubicin and vincristine in lymphoma cells. CONCLUSIONS Vincristine increases the susceptibility of human iPSC-CMs to doxorubicin-associated injury, accompanied by cytoskeletal stress-related signaling and mitochondrial alterations. SGLT2 inhibition partially attenuated these cellular responses while preserving anti-tumor activity, suggesting a potential strategy for mitigating chemotherapy-associated cardiotoxicity.
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Chang et al. (2026) studied Chemotherapy-associated cardiotoxicity. Doxorubicin, vincristine, and SGLT2 inhibitors vs. Doxorubicin or vincristine alone was evaluated on Cellular apoptosis, signaling, and mitochondrial function. Vincristine potentiated doxorubicin-induced apoptosis in human iPSC-derived cardiomyocytes, which was partially attenuated by SGLT2 inhibition without reducing anti-tumor efficacy.
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