Journal
PHYTOTHERAPY RESEARCH
Volume 27, Issue 10, Pages 1481-1488Publisher
WILEY-BLACKWELL
DOI: 10.1002/ptr.4888
Keywords
luteolin; lung metastasis; Raf kinase; PI3K; MMP-2/9
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Funding
- Next-Generation BioGreen 21 Program (Plant Molecular Breeding Center) [PJ008187]
- Rural Development Administration, Republic of Korea
- National Research Foundation of Korea (NRF)
- Korea government (MEST) [2010-0029233]
- World Class University Program [R31-2008-00-1-56-0]
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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 50mg/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. Copyright (c) 2012 John Wiley & Sons, Ltd.
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