Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway

Mohamed S. Dabour, Ibrahim Y Abdelgawad, Marianne K Grant, Engie S. El-Sawaf, Beshay N. Zordoky

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Carfilzomib (CFZ) is a proteasome inhibitor approved for relapsed/refractory multiple myeloma (MM) but its clinical use is limited by cardiovascular toxicity. The mechanisms of CFZ-induced cardiovascular toxicity are not fully understood but endothelial dysfunction may be a common denominator. Here, we first characterized the direct toxic effects of CFZ on endothelial cells (HUVECs and EA.hy926 cells) and tested whether SGLT2 inhibitors, known to have cardioprotective effects, can protect against CFZ-induced toxicity. To determine the chemotherapeutic effect of CFZ in the presence of SGLT2 inhibitors, MM and lymphoma cells were treated with CFZ with or without canagliflozin. CFZ decreased cell viability and induced apoptotic cell death in endothelial cells in a concentration-dependent manner. CFZ also upregulated ICAM-1 and VCAM-1 and downregulated VEGFR-2. These effects were associated with the activation of Akt and MAPK pathways, inhibition of p70s6k, and downregulation of AMPK. Canagliflozin, but not empagliflozin or dapagliflozin, protected endothelial cells from CFZ-induced apoptosis. Mechanistically, canagliflozin abrogated CFZ-induced JNK activation and AMPK inhibition. AICAR (an AMPK activator) protected from CFZ-induced apoptosis, and compound C (an AMPK inhibitor) abrogated the protective effect of canagliflozin, strongly suggesting that AMPK mediates these effects. Canagliflozin did not interfere with the anticancer effect of CFZ in cancer cells. In conclusion, our findings demonstrate for the first time the direct toxic effects of CFZ in endothelial cells and the associated signaling changes. Canagliflozin abrogated the apoptotic effects of CFZ in endothelial cells in an AMPK-dependent mechanism, without interfering with its cytotoxicity in cancer cells.

Original languageEnglish (US)
Article number114907
JournalBiomedicine and Pharmacotherapy
Volume164
DOIs
StatePublished - Aug 2023

Bibliographical note

Funding Information:
This research is supported by the SURRGE Award from the University of Minnesota College of Pharmacy to B.N.Z. M.S.D. is supported by a scholarship from the Egyptian Ministry of Higher Education . I.Y.A. is supported by Doctoral Dissertation Fellowship (University of Minnesota) and Bighley Graduate Fellowship (University of Minnesota College of Pharmacy). E.S.E. is supported by a scholarship from the United States Agency for International Development (USAID).

Publisher Copyright:
© 2023 The Authors

Keywords

  • AMPK
  • Canagliflozin
  • Carfilzomib
  • Endothelial Cells
  • SGLT2 inhibitors

PubMed: MeSH publication types

  • Journal Article

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