Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

Mitsuko Takenaga; Yuki Yamamoto; Tomoki Takeuchi; Yuki Ohta; Yukie Tokura; Akemi Hamaguchi; Daisuke Asai; Hideki Nakashima; Shinya Oishi; Nobutaka Fujii

doi:10.1016/j.bbrc.2015.05.029

Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

Biochem Biophys Res Commun. 2015 Jul 31;463(3):222-8. doi: 10.1016/j.bbrc.2015.05.029. Epub 2015 May 19.

Authors

Affiliations

¹ Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: m2take@marianna-u.ac.jp.
² Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: yukiyama@diary.ocn.ne.jp.
³ Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: takeuchi.tomoki.32v@st.kyoto-u.ac.jp.
⁴ Department of Pharmacology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: yuki-o@marianna-u.ac.jp.
⁵ 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.
⁶ Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: hamaguch@marianna-u.ac.jp.
⁷ Department of Microbiology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: asai@marianna-u.ac.jp.
⁸ Department of Microbiology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Electronic address: hidekin@marianna-u.ac.jp.
⁹ Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: soishi@pharm.kyoto-u.ac.jp.
¹⁰ Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: nfujii@pharm.kyoto-u.ac.jp.

PMID: 25998394
DOI: 10.1016/j.bbrc.2015.05.029

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.

Keywords: Apoptosis; Human ovarian cancer; Kinesin spindle protein; Neurotoxicity; Securin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / therapeutic use*
Antineoplastic Agents / toxicity
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Humans
Kinesins / antagonists & inhibitors*
Kinesins / metabolism
Mice, Inbred BALB C
Mitosis / drug effects
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Ovary / drug effects*
Ovary / metabolism
Ovary / pathology
Proto-Oncogene Proteins c-bcl-2 / metabolism
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents
KIF11 protein, human
Proto-Oncogene Proteins c-bcl-2
Reactive Oxygen Species
Kinesins