Vincristine enhances doxorubicin cardiotoxicity in human iPSC-derived cardiomyocytes: Partial attenuation by SGLT2 inhibition.

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.