The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells

Leukemia. 2003 Oct;17(10):2036-45. doi: 10.1038/sj.leu.2403109.


Interactions between the small molecule Bcl-2 inhibitor HA14-1 and proteasome inhibitors, including bortezomib (Velcade; formerly known as PS-341) and MG-132, have been examined in human multiple myeloma cells. Sequential (but not simultaneous) exposure of MM.1S cells to bortezomib or MG-132 (10 h) followed by HA14-1 (8 h) resulted in a marked increase in mitochondrial injury (loss of DeltaPsim, cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), activation of procaspases-3, -8, and -9, and Bid, induction of apoptosis, and loss of clonogenicity. Similar interactions were observed in U266 and MM.1R dexamethasone-resistant myeloma cells. These events were associated with Bcl-2 cleavage, Bax, Bak, and Bad accumulation, mitochondrial translocation of Bax, abrogation of Mcl-1, Bcl-xL, and XIAP upregulation, and a marked induction of JNK and p53. Bortezomib/HA14-1 treatment triggered an increase in reactive oxygen species (ROS), which, along with apoptosis, was blocked by the free radical scavenger N-acetyl-L-cysteine (L-NAC). L-NAC also opposed bortezomib/HA14-1-mediated JNK activation, upregulation of p53 and Bax, and release of cytochrome c and Smac/DIABLO. Finally, bortezomib/HA14-1-mediated apoptosis was unaffected by exogenous IL-6. Together, these findings indicate that sequential exposure of myeloma cells to proteasome and small molecule Bcl-2 inhibitors such as HA14-1 may represent a novel therapeutic strategy in myeloma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / physiology*
  • Boronic Acids / toxicity*
  • Bortezomib
  • Cell Division / drug effects
  • Cysteine Endopeptidases
  • Cytochrome c Group / analysis
  • Dexamethasone / pharmacology
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multiple Myeloma
  • Protease Inhibitors / toxicity*
  • Proteasome Endopeptidase Complex
  • Pyrazines / toxicity*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Boronic Acids
  • Cytochrome c Group
  • Multienzyme Complexes
  • Protease Inhibitors
  • Pyrazines
  • Bortezomib
  • Dexamethasone
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex