title: Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor.
abstract: Among synthetic kinesin spindle protein (KSP) inhibitor compounds, KPYB10602, a six-member lactam-fused carbazole derivative was the most potent in vitro against cell growth of human ovarian cancer, A2780. KPYB10602 caused dose-dependent suppression of tumor growth in vivo. Mitotic arrest due to KPYB10602 was confirmed in vitro, and was characterized by inhibition of securin degradation. Apoptosis after mitotic arrest was associated with an increase in the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Increase of reactive oxygen species (ROS) and caspase pathway were also involved. Furthermore, KPYB10602 caused little neurotoxicity in vivo. Therefore, KPYB10602 could be a promising candidate as an anti-tumor agent with reduced adverse events for treating human ovarian cancer.
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: m2take@marianna-u.ac.jp.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Takenaga
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: yukiyama@diary.ocn.ne.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: takeuchi.tomoki.32v@st.kyoto-u.ac.jp.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Pharmacology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: yuki-o@marianna-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: yukie-t@marianna-u.ac.jp.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Tokura
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: hamaguch@marianna-u.ac.jp.
authors.forename: Akemi
authors.initials: A
authors.lastname: Hamaguchi
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: asai@marianna-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Asai
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: hidekin@marianna-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: soishi@pharm.kyoto-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: nfujii@pharm.kyoto-u.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016547:Kinesins
keywords: Apoptosis; Human ovarian cancer; Kinesin spindle protein; Neurotoxicity; Securin