Bortezomib-induced apoptosis in the treatment of non-small cell lung cancer

Despite advances in the past few decades, current chemotherapy regimens have had only limited efficacy with modest survival benefit and significant toxicity in non-small cell lung cancer (NSCLC) patients. Novel therapies, especially those targeting cell signaling pathways, are now under extensive investigation against many tumor types. Proteasome inhibition, one of the novel cancer therapies, has been shown to have widespread ability to induce apoptosis in vitro in a broad spectrum of tumor cell lines. Bortezomib (Velcade) is the first proteasome inhibitor to enter clinical trials. It has demonstrated encouraging efficacy against multiple myeloma, where it is now an approved therapy. In in vitro studies of lung cancer, bortezomib has been found to induce marked apoptosis by itself or when used together with other novel therapy agents or chemotherapy agents. Despite these promising results, bortezomib has not shown great efficacy against lung cancer in clinical trials. In this review, we describe the role of the proteasome in cell homeostasis and apoptosis, the molecular mechanisms of bortezomib-induced apoptosis in preclinical studies of NSCLC cells, and its efficacy to date in the clinical trials. We consider possible reasons why proteasome inhibition may not be as effective in lung cancer and ways in which the efficacy might be improved in the future.