title: Azaspirene analogs inhibit the growth of human uterine carcinosarcoma in vitro and in vivo.
abstract: Uterine carcinosarcoma is a highly aggressive gynecological neoplasm that responds poorly to conventional chemotherapy and radiotherapy. Recent studies have shown high angiogenic activities of this tumor, hence anti-angiogenic approaches are expected to provide new treatment strategies for this tumor. In previous work, azaspirene was isolated from Neosartorya sp. fungi, and in vitro anti-angiogenic activities were shown. In the present study, the anti-angiogenic effects of azaspirene analogs, synthetic molecules with a shorter ethyl group replacing a hexadienyl side-chain of the natural compound, were assessed in vitro using human umbilical vein endothelial cells (HUVECs) co-cultured with FU-MMT-3 human uterine carcinosarcoma cells. The anti-tumor and anti-angiogenic effects of these analogs were also evaluated in vivo using FU-MMT-3 xenografted tumors in nude mice. The azaspirene analogs inhibited the tube formation of HUVECs induced by FU-MMT-3 cells in vitro and significantly suppressed tumor growth in vivo compared to the untreated group (control). A significant reduction of the microvessel density in tumors was observed, in comparison to the control. No apparent toxicity, including body loss, was observed in any mice treated in this study. These azaspirene analogs may be effective against uterine carcinosarcoma, possibly acting via potent anti-angiogenic effects.
authors.affiliation: Department of Health and Welfare, International University of Health and Welfare, Fukuoka, Japan Division of Gynecology in Preventive Medicine, Fukuoka Sanno Hospital, Sawara-ku, Fukuoka, Japan emoto1209@gmail.com.
authors.forename: Makoto
authors.initials: M
authors.lastname: Emoto
authors.affiliation: Department of Pathology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yano
authors.affiliation: Department of Health and Welfare, International University of Health and Welfare, Fukuoka, Japan.
authors.forename: Batsuren
authors.initials: B
authors.lastname: Choijamts
authors.affiliation: Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Hirasawa
authors.affiliation: Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Wakamori
authors.affiliation: Department of Applied Chemistry, School of Science and Technology, Meiji University, Kawasaki, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Aizawa
authors.affiliation: Department of Pathology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
authors.affiliation: Department of Anatomy, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.
authors.forename: Katsuro
authors.initials: K
authors.lastname: Tachibana
authors.affiliation: Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanomata
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D002296:Carcinosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011760:Pyrrolidinones / Q000008:administration & dosage*; D013141:Spiro Compounds / Q000008:administration & dosage*; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D011760:Pyrrolidinones; D013141:Spiro Compounds; D042461:Vascular Endothelial Growth Factor A; C469812:azaspirene
keywords: Uterine carcinosarcoma; anti-angiogenic therapy; azaspirene