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

• Published in: Annals of the New York Academy of Sciences Vol. 1095; no. 1; pp. 598 - 611
• Main Authors: KIM, JIN-HYUNG, LEE, EUN-OK, LEE, HYO-JUNG, KU, JIN-SOOK, LEE, MIN-HO, YANG, DEOK-CHUN, KIM, SUNG-HOON
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.01.2007
• Subjects: Akt; Animals; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - pathology; caspase; Caspases - metabolism; Caspases - physiology; Cell Line, Tumor; Cell Proliferation - drug effects; Enzyme Activation - drug effects; extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Growth Inhibitors - administration & dosage; Lewis lung carcinoma; luteolin; Luteolin - administration & dosage; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - physiology
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1397.102_2

:  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 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.