Background
The prognosis of lung cancer is very poor and hence new therapeutic strategies are urgently desired. In this study, we searched for efficacious Smac mimetic-based combination therapies with biomarkers to predict responses for non-small cell lung cancer (NSCLC).
Conclusion
Our results indicate that IFNγ and Smac mimetics can synergize to induce apoptosis of NSCLC cells and suggest that IFNγ and Smac mimetic regimen may be a novel and efficacious apoptosis targeted therapy with biomarkers to predict responses for NSCLC cells.
Methods
NSCLC cell lines and normal human alveolar epithelial cells were treated with Smac mimetics plus IFNγ or other agonists and cell viabilities were assessed by MTS assay, cell counting, flow cytometry and cell colony assay. Western blot analysis was performed to assess the cleavage (activation) of caspases and expression of signaling molecules. Caspase activity was determined to verify caspase activation. The pathways involved in NSCLC cell death were investigated using specific inhibitors.
Results
We found that IFNγ could cooperate with various Smac mimetics to trigger a profound apoptosis in a number of NSCLC cell lines that are competent for IFNγ signaling (i.e. expressing IFNγ receptor-1 and STAT1) but have low expression levels of inhibitor of apoptosis proteins survivin and livin without harming normal human lung epithelial cells. IFNγ co-treatment with a novel class dimeric Smac mimetic AZD5582 eradicated NSCLC cell colony formation. Unlike IFNγ, IFNα, IFNλ, TNFα, or TRAIL alone or plus AZD5582 had minor effects on NSCLC cell viability. IFNγ/AZD5582-induced cell death in NSCLC cells was independent of TNFα autocrine but relied on apoptosis mediated by JAK kinase, caspase 8 and RIPK1 pathways.