title: 15α-methoxypuupehenol Induces Antitumor EffectsIn VitroandIn Vivoagainst Human Glioblastoma and Breast Cancer Models.
abstract: Studies with 15α-methoxypuupehenol (15α-MP), obtained from the extracts ofHyrtiosspecies, identified putative targets that are associated with its antitumor effects against human glioblastoma and breast cancer. In the human glioblastoma (U251MG) or breast cancer (MDA-MB-231) cells, treatment with 15α-MP repressed pY705Stat3, pErk1/2, pS147CyclinB1, pY507Alk (anaplastic lymphoma kinase), and pY478ezrin levels and induced pS10merlin, without inhibiting pJAK2 (Janus kinase) or pAkt induction. 15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and glioblastoma (U251MG) lines and glioblastoma patient-derived xenograft cells (G22) that harbor aberrantly active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3fl/fl) lines that do not harbor constitutively active Stat3 or the Stat3-null (Stat3-/-) mouse astrocytes. 15α-MP-treated U251MG cells have severely impaired F-actin organization and altered morphology, including the cells rounding up, and undergo apoptosis, compared with a moderate, reversible morphology change observed for similarly treated mouse astrocytes. Treatment further inhibited U251MG or MDA-MB-231 cell proliferation, anchorage-independent growth, colony formation, and migrationin vitrowhile only moderately or weakly affecting MCF7 cells or normal mouse astrocytes. Oral gavage delivery of 15α-MP inhibited the growth of U251MG subcutaneous tumor xenografts in mice, associated with apoptosis in the treated tumor tissues. Results together suggest that the modulation of Stat3, CyclinB1, Alk, ezrin, merlin, and Erk1/2 functions contributes to the antitumor effects of 15α-MP against glioblastoma and breast cancer progression.Mol Cancer Ther; 16(4); 601-13. ©2017 AACR.
authors.affiliation: Cancer Biology and Natural Products Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.
authors.forename: Tyvette S
authors.initials: TS
authors.lastname: Hilliard
authors.affiliation: Cancer Biology and Natural Products Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Miklossy
authors.affiliation: Department of Chemistry, University of Hawai'i at Manoa, Honolulu, Hawaii.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chock
authors.affiliation: Cancer Biology and Natural Products Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.affiliation: Department of Chemistry, University of Hawai'i at Manoa, Honolulu, Hawaii.
authors.forename: Philip
authors.initials: P
authors.lastname: Williams
authors.affiliation: Cancer Biology and Natural Products Program, University of Hawai'i Cancer Center, Honolulu, Hawaii. jturkson@cc.hawaii.edu.
authors.forename: James
authors.initials: J
authors.lastname: Turkson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056744:Cyclin B1 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D051379:Mice; D050796:STAT3 Transcription Factor / Q000235:genetics; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C400144:15alpha-methoxypuupehenol; C534699:CCNB1 protein, human; D056744:Cyclin B1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012717:Sesquiterpenes