Abstract
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 language | English |
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Pages (from-to) | 1046-1053 |
Number of pages | 8 |
Journal | Molecular Cancer Therapeutics |
Volume | 6 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2007 |
Keywords
- 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