Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molecular 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 IC50 of 12 μM. Luteolin effectively increased Annexin-V-positive cells aswell as sub G ₁ DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin effectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochondrial membrane potential was reduced by luteolin as seen on fluorescence microscopy. Luteolin downregulated the expression of extracellular 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.