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 microM. Luteolin effectively increased Annexin-V-positive cells as well as sub G1 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.
Kim
Jin-Hyung
JH
Department of Oncology, Graduate School of East-West Medical Science, Kyung Hee University, 1 Seochunri, Yongin 449-701, Republic of Korea.
Lee
Eun-Ok
EO
Lee
Hyo-Jung
HJ
Ku
Jin-Sook
JS
Lee
Min-Ho
MH
Yang
Deok-Chun
DC
Kim
Sung-Hoon
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D047311:Luteolin