Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway
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,...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223006972 |
| _version_ | 1797801851600502784 |
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| author | Mohamed S. Dabour Ibrahim Y. Abdelgawad Marianne K.O. Grant Engie S. El-Sawaf Beshay N. Zordoky |
| author_facet | Mohamed S. Dabour Ibrahim Y. Abdelgawad Marianne K.O. Grant Engie S. El-Sawaf Beshay N. Zordoky |
| author_sort | Mohamed S. Dabour |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T04:56:49Z |
| format | Article |
| id | doaj.art-835681aea5364cf1a2da5944f8ea9ab4 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-13T04:56:49Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-835681aea5364cf1a2da5944f8ea9ab42023-06-18T05:00:39ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-08-01164114907Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathwayMohamed S. Dabour0Ibrahim Y. Abdelgawad1Marianne K.O. Grant2Engie S. El-Sawaf3Beshay N. Zordoky4Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, 31111 Tanta, EgyptDepartment of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USADepartment of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USADepartment of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, EgyptDepartment of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Correspondence to: 7-115 Weaver-Densford Hall 308 Harvard St. SE, Minneapolis, MN 55455, USA.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.http://www.sciencedirect.com/science/article/pii/S0753332223006972CarfilzomibSGLT2 inhibitorsCanagliflozinEndothelial CellsAMPK |
| spellingShingle | Mohamed S. Dabour Ibrahim Y. Abdelgawad Marianne K.O. Grant Engie S. El-Sawaf Beshay N. Zordoky Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway Biomedicine & Pharmacotherapy Carfilzomib SGLT2 inhibitors Canagliflozin Endothelial Cells AMPK |
| title | Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway |
| title_full | Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway |
| title_fullStr | Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway |
| title_full_unstemmed | Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway |
| title_short | Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway |
| title_sort | canagliflozin mitigates carfilzomib induced endothelial apoptosis via an ampk dependent pathway |
| topic | Carfilzomib SGLT2 inhibitors Canagliflozin Endothelial Cells AMPK |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223006972 |
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