title: 4-methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells.
abstract: Hyaluronan (HA), a major component of the extracellular matrix (ECM), is             synthesized by HA synthase (HAS) 1, HAS2 and HAS3 and is intricately involved             in cell growth and metastasis. The HA synthesis inhibitor 4-methylumbelliferone             (4-MU) has been reported to exhibit anticancer properties in various types of             malignant tumors. However, the underlying mechanisms at the molecular and cellular             levels remain unclear. In this study, to establish an animal model for studying             the function of HA in human breast cancer, we investigated the antitumor effects             of 4-MU using canine mammary tumor (CF33) cells. First, we investigated the effects             of 4-MU on HA production in CF33 cells. Quantitative analysis of HA in culture             media showed that 4-MU inhibited HA synthesis, accompanied by downregulation of             HAS2 mRNA levels, in a dose-dependent manner at 24-72 h. Additionally, we observed             a 4-MU-mediated decrease in the extent of the cell-associated HA matrix. We examined             the effect of 4-MU on cell growth and apoptosis in CF33 cells. 4-MU markedly inhibited             cell proliferation and induced apoptosis in CF33 cells. In particular, our experiments             showed that the mechanism of 4-MU-induced apoptosis in CF33 cells involved increased             levels of expression of pro-apoptotic BAX mRNA and protein molecules. These data             suggest that 4-MU may be a candidate therapeutic agent for the treatment of canine             mammary tumors. Furthermore, this study provides the first indication that the             canine mammary tumor may be a suitable model for comparative study of the function             of HA in human breast cancer.
authors.affiliation: Laboratory of Veterinary Pharmacology, Nihon University College of Bioresource Sciences, 1866 Kameino, Fujisawa, Kanagawa 252-8510, Japan. saitou.teruyoshi@nihon-u.ac.jp
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Dai
authors.initials: D
authors.lastname: Tamura
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Makita
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ariyama
authors.forename: Keiji
authors.initials: K
authors.lastname: Komiyama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Ryuji
authors.initials: R
authors.lastname: Asano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D006923:Hymecromone / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D007202:Indicators and Reagents; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases