ヨゴサワ　シンゴ   YOGOSAWA Shingo   与五沢　真吾    所属   埼玉医科大学  保健医療学部 臨床検査学科    職種   准教授
論文種別	学術雑誌(原著)
言語種別	英語
査読の有無	査読あり
表題	Histone Deacetylase Inhibitors and 15-Deoxy-Delta(12,14)-Prostaglandin J(2) Synergistically Induce Apoptosis
掲載誌名	正式名：CLINICAL CANCER RESEARCH ISSNコード：1078-0432
出版社	AMER ASSOC CANCER RESEARCH
巻・号・頁	16(8),2320-2332頁
著者・共著者	Makoto Koyama,Yasuyuki Izutani,Ahmed E. Goda,Taka-aki Matsui,Mano Horinaka,Mitsuhiro Tomosugi,Jun Fujiwara,Yoshitaka Nakamura,Miki Wakada,Shingo Yogosawa,Yoshihiro Sowa,Toshiyuki Sakai
発行年月	2010/04
概要	Purpose: The clinically relevant histone deacetylase inhibitors (HDI) valproic acid (VPA) and suberoylanilide hydroxamic acid exert variable antitumor activities but increase therapeutic efficacy when combined with other agents. The natural endogenous ligand of peroxisome proliferator-activated receptor. 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a potent antineoplastic agent. Therefore, we investigated whether these HDIs in combination with 15d-PGJ(2) could show synergistic antitumor activity in colon cancer DLD-1 cells. Experimental Design: Cell viability was determined using a Cell Counting Kit-8 assay. Apoptosis and reactive oxygen species (ROS) generation were determined using flow cytometry analysis. Western blotting and real-time reverse transcription-PCR analysis were carried out to investigate the expression of apoptosis-related molecules. Mice bearing DLD-1 xenograft were divided into four groups (n = 5) and injected everyday (i.p.) with diluent, VPA (100 mg/kg), 15d-PGJ(2) (5 mg/kg), or a combination for 25 days. Results: HDI/15d-PGJ(2) cotreatments synergistically induced cell death through caspase-dependent apoptosis in DLD-1 cells. Moreover, HDIs/15d-PGJ(2) caused histone deacetylase inhibition, leading to subsequent ROS generation and endoplasmic reticulum stress to decrease the expression of antiapoptotic molecules Bcl-X-L and XIAP and to increase that of proapoptotic molecules CAAT/enhancer binding protein homologous protein and death receptor 5. Additionally, VPA/15d-PGJ(2) cotreatment induced ROS-dependent apoptosis in other malignant tumor cells and was more effective than a VPA or 15dPGJ(2) monotherapy in vivo. Conclusions: Cotreatments with the clinically relevant HDIs and the endogenous peroxisome proliferator-activated receptor. ligand 15d-PGJ(2) are promising for the treatment of a broad spectrum of malignant tumors. Clin Cancer Res; 16(8); 2320-32. (C) 2010 AACR.
DOI	10.1158/1078-0432.CCR-09-2301
PMID	20371690