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This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). Phosphorylation of both of mTOR's downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaol's effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.

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Background: This prospective observational study estimated the effect of prognostic factors, particularly continued smoking during therapy, on survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine-platinum. Further, prognostic factors were used to build a survival model to improve prognosis prediction in naturalistic clinical settings.Methods: Eligibility criteria included: Stage IIIB/IV NSCLC, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. A Cox regression model was constructed and validated by randomizing patients into two datasets (Construction [C]:Validation [V]; 3:1 ratio). Country, disease stage, hypercalcemia, “N” factor, weight reduction, performance status, and superior vena cava obstruction were pre-defined variables forced into the model. Continued smoking was tested with adjustment for these variables.Results: One thousand two hundred and fourteen patients (C=891 and V=323) were enrolled. The final predictive model, established in the Construction dataset, identified four significant (p≤0.05) and independent predictors of survival, which were disease stage, performance status, gemcitabine-platinum regimen, and T-stage. Smoking during therapy was not significantly associated with survival (Hazard Ratio [95% CI]: 0.955 [0.572, 1.596], p=0.8618; versus never smokers).Conclusions: Although continued smoking during therapy was not significantly associated with shorter survival, the model developed in this study forms an evidence-based approach to assessing prognosis in advanced stage NSCLC.