Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells

Abstract

Carfilzomib (CFZ), a second-generation proteasome inhibitor, is a key treatment for multiple myeloma (MM), but its use is associated with significant cardiovascular adverse events (CVAEs), including heart failure and hypertension. Endothelial dysfunction is believed to contribute to these CVAEs. Building on our previous findings that CFZ induces endothelial toxicity and that canagliflozin protects against CFZ-induced endothelial apoptosis, this study aimed to evaluate CFZ-induced endoplasmic reticulum (ER) stress and autophagy in endothelial and MM cells, as well as the impact of canagliflozin on these processes and its impact on the anticancer effects of CFZ in MM cells. Endothelial cells (HUVECs and EA.hy926) and multiple myeloma cells (RPMI8226) were treated with 0.5 µM CFZ, either alone or in combination with canagliflozin (5–20 µM), to assess the effects on ER stress and autophagy in both cell types. CFZ induced ER stress in endothelial and MM cells. In endothelial cells, canagliflozin mitigated CFZ-induced markers of ER stress, while unexpectedly upregulating CFZ-induced CHOP. Whereas, in MM cells, canagliflozin did not alter CFZ-induced ER stress, but instead further upregulated CFZ-induced ATF-4. In addition, CFZ induced autophagy in endothelial cells while inhibiting it in MM cells. Canagliflozin abrogated CFZ-induced autophagy in endothelial cells. In striking contrast to its effects in endothelial cells, canagliflozin enhanced the cytotoxic effects of CFZ in MM cells. Intriguingly, in an innovative co-culture system, canagliflozin enhanced CFZ-induced apoptosis in MM cells while protecting endothelial cells. These findings underscore the dual role of canagliflozin in reducing CFZ-induced endothelial toxicity, while enhancing its cytotoxic effect in MM.