title: Isoliquiritigenin 2'-methyl ether induces growth inhibition and apoptosis in oral cancer cells via heme oxygenase-1.
abstract: We previously reported that a chloroform extract of Caesalpinia sappan L. induces apoptosis in oral cancer cells but not in normal epithelial cell lines. In the present study, we explored the effects of a single compound isolated from C. sappan heartwood, isoliquiritigenin 2'-methyl ether (ILME), on cultured primary and metastatic oral cancer cell lines using MTT assays, fluorescence microscopy, flow cytometry, and Western blotting. ILME inhibited the growth of the oral cancer cells in a time- and dose-dependent manner. The major mechanism of growth inhibition was apoptosis induction, as shown by flow cytometric analysis of sub-G(1)-phase arrest and by annexin V-FITC and propidium iodide staining. ILME time-dependently activated NF-kappaB transcription factors, phospholated the MAP kinases JNK (c-Jun N-terminal kinase) and ERK (extracellular signal-regulated kinase). Furthermore, ILME treatment upregulated HO-1 expression though activation of Nrf2 (NF-E2-related factor 2) pathway, and induced the expression of heme oxygenase-1 (HO-1). Tin protoporphyrin, an HO-1 inhibitor, dose-dependently attenuated the growth-inhibitory effect of ILME and blocked ILME-induced expression of the p21 and p53 cell cycle-regulatory proteins. These results provide the first evidence that the anti-oral cancer effects of ILME may involve a mechanism in which HO-1 is upregulated via a pathway involving MAP kinases, NF-kappaB, and Nrf2. Thus, ILME could be considered to be a potential chemotherapeutic target for anti-oral cancer treatment strategies.
authors.affiliation: Department of Oral and Maxillofacial Pathology, Wonkwang University, Iksan, South Korea.
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Lee
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
authors.forename: Hyun-Dae
authors.initials: HD
authors.lastname: Lim
authors.forename: Ren-Bo
authors.initials: RB
authors.lastname: An
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D054462:p21-Activated Kinases / Q000187:drug effects / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; C550177:isoliquiritigenin 2'-methyl ether; D002599:Chalcone; D051547:Heme Oxygenase-1; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases