gw-5074 and Lung-Neoplasms

Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chromones; Indoles; Lung Neoplasms; Luteolin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Morpholines; Neoplasm Invasiveness; Neoplasm Metastasis; Phenols; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; raf Kinases