title: Hypericum androsaemum water extract inhibits proliferation in human colorectal cancer cells through effects on MAP kinases and PI3K/Akt pathway.
abstract: MAP kinase and PI3K/Akt signalling pathways are commonly altered in colorectal carcinoma (CRC) leading to tumor growth due to increased cell proliferation and inhibition of apoptosis. Several species of the genus Hypericum are used in Portugal to prepare herbal teas to which digestive tract effects are attributed. In the present study, the antiproliferative and proapoptotic effects of the water extracts of H. androsaemum (HA) and H. perforatum (HP) were investigated in two human colon carcinoma-derived cell lines, HCT15 and CO115, which harbour activating mutations of KRAS and BRAF, respectively. Contrarily to HP, HA significantly inhibited cell proliferation and induced apoptosis in both cell lines. HA decreased BRAF and phospho-ERK expressions in CO115, but not in HCT15. HA also decreased Akt phosphorylation in CO115 and induced p38 and JNK in both cell lines. HA induced cell cycle arrest at S and G2/M phases as well as caspase-dependent apoptosis in both cell lines. Chlorogenic acid (CA), the main phenolic compound present in the HA extract and less represented in the HP water extract, did, however, not show any of those effects when used individually. In conclusion, water extract of HA, but not of HP, controlled CRC proliferation and specifically acted on mutant and not wild-type BRAF. The effect of HA was, however, not due to CA alone.
authors.affiliation: CBMA - Centre of Molecular and Environmental Biology/Department of Biology, University of Minho, 4710-057 Braga, Portugal.
authors.forename: Cristina P R
authors.initials: CP
authors.lastname: Xavier
authors.forename: Cristovao F
authors.initials: CF
authors.lastname: Lima
authors.forename: Manuel
authors.initials: M
authors.lastname: Fernandes-Ferreira
authors.forename: Cristina
authors.initials: C
authors.lastname: Pereira-Wilson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000032:analysis; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D014867:Water; D018631:ras Proteins / Q000032:analysis
chemical_list: C117307:KRAS protein, human; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D014867:Water; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins