Bortezomib induces autophagic death in proliferating human endothelial cells

Daniela Belloni, Lorenzo Veschini, Chiara Foglieni, Giacomo Dell'Antonio, Federico Caligaris-Cappio, Marina Ferrarini, Elisabetta Ferrero

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60 Citations (Scopus)


The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

Original languageEnglish
Pages (from-to)1010-8
Number of pages9
JournalExperimental Cell Research
Issue number6
Publication statusPublished - 1 Apr 2010


  • Adenine
  • Angiogenesis Inhibitors
  • Animals
  • Antineoplastic Agents
  • Autophagy
  • Boronic Acids
  • Bortezomib
  • Cell Proliferation
  • Cells, Cultured
  • Endothelial Cells
  • Fibroblast Growth Factors
  • Humans
  • Microtubule-Associated Proteins
  • Multiple Myeloma
  • Protease Inhibitors
  • Pyrazines
  • Reactive Oxygen Species
  • Journal Article
  • Research Support, Non-U.S. Gov't


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