Caspase Activation and Extracellular Signal-Regulated Kinase/Akt Inhibition Were Involved in Luteolin-Induced Apoptosis in Lewis Lung Carcinoma Cells

摘要

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molec ular mechanism of luteolin and its effect on in vivo tumor growth of Lewis lung carcinoma (LLC) cells. Luteolin exhibited antiproliferative activity against LLC cells with IC_(50) of 12 μM. Luteolin effectively in creased Annexin-V-positive cells as well as sub G_1 DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin ef fectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochon drial membrane potential was reduced by luteolin as seen on fluores cence microscopy. Luteolin downregulated the expression of extracellu lar signal-regulated kinase (ERK) and Akt in a concentration-dependent manner. In addition, luteolin significantly inhibited the growth of LLC cells implanted on the flank of mice to 40% and 60% of untreated control group values at 2 mg/kg and 10 mg/kg, respectively. Similarly, luteolin significantly reduced the expression of proliferating cell nuclear antigen (PCNA) as well as increased the expression of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in tumor section of LLC-bearing mice as determined by immunohistochemistry. Taken together, these results suggest that luteolin exerts antitumor activity by caspase activation and ERK/Akt inhibition.