Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460

Jens Voortman, Agnieszka Checinska, Giuseppe Giaccone, Jose A Rodriguez, Frank A E Kruyt

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45 Citations (Scopus)


Defects in the apoptotic machinery may contribute to chemoresistance of non-small cell lung cancer (NSCLC) cells. We have previously showed a deficiency in mitochondria-dependent caspase-9 activation in NSCLC H460 cells after exposure to cisplatin, a drug widely used to treat NSCLC. Here we show that, unlike cisplatin, the novel anticancer agent bortezomib efficiently induces caspase-9 activation and apoptosis in H460 cells. A comparative analysis of molecular events underlying cell death in bortezomib-treated versus cisplatin-treated H460 cells revealed that bortezomib, but not cisplatin, caused a rapid and abundant release of cytochrome c and Smac/DIABLO from mitochondria. This was associated with a marked increase in levels of the BH3-only proapoptotic protein Noxa and the antiapoptotic protein Mcl-1. Taken together, our data show that bortezomib, by promoting a proapoptotic shift in the levels of proteins involved in mitochondrial outer-membrane permeabilization, is a potent activator of the mitochondrial pathway of apoptosis in NSCLC cells. Our preclinical results support further investigation of bortezomib-based therapies as a possible new treatment modality for NSCLC.

Original languageEnglish
Pages (from-to)1046-1053
Number of pages8
JournalMolecular Cancer Therapeutics
Issue number3
Publication statusPublished - Mar 2007


  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Blotting, Western
  • Boronic Acids/pharmacology
  • Bortezomib
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Caspase Inhibitors
  • Caspases/metabolism
  • Cisplatin/pharmacology
  • Cytochromes c/metabolism
  • Humans
  • Lung Neoplasms/drug therapy
  • Mitochondria/drug effects
  • Proto-Oncogene Proteins c-bcl-2/metabolism
  • Pyrazines/pharmacology
  • Tumor Cells, Cultured/drug effects
  • Up-Regulation

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