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

• Published in: Molecular cancer therapeutics Vol. 6; no. 3; pp. 1046 - 1053
• Main Authors: Voortman, Jens, Checinska, Agnieszka, Giaccone, Giuseppe, Rodriguez, Jose A, Kruyt, Frank A E
• Format: Journal Article
• Language: English
• Published: United States 01-03-2007
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Blotting, Western; Boronic Acids - pharmacology; Bortezomib; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspase Inhibitors; Caspases - metabolism; Cisplatin - pharmacology; Cytochromes c - metabolism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mitochondria - drug effects; Mitochondria - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrazines - pharmacology; Tumor Cells, Cultured - drug effects; Up-Regulation
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0577

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.