title: NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect.
abstract: Herein, we investigated therapeutic potential of a novel histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in prostate cancer. Hormone-sensitive prostate cancer cells, (LNCaP) and castration resistant cancer cells (PC3 and PCai1) were treated with NCL1, and LSD1 expression and cell viability were assessed. Prostate cancer cells showed strong LSD1 expression, and cell viability was decreased by NCL1. ChIP analysis showed that NCL1 induced H3K9me2 accumulation at the promoters of androgen-responsive genes. NCL1 also induced G1 cell cycle arrest and apoptosis. In addition, autophagosomes and autolysosomes were induced by NCL1 treatment in LNCaP. Furthermore, LC3-II expression was significantly increased by NCL1 and chloroquine. In mice injected subcutaneously with PCai1 and intraperitoneally with NCL1, tumor volume was reduced with no adverse effects in NCL1-treated mice. Finally, LSD1 expression in human cancer specimens was significantly higher than that in normal prostate glands. In conclusion, NCL1 effectively suppressed prostate cancer growth without adverse events. We suggest that NCL1 is a potential therapeutic agent for hormone-resistant prostate cancer.
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Etani
authors.affiliation: Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Naiki
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ando
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kawai
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tozawa
authors.affiliation: Institute of Drug Discovery Science, Nagoya City University, Graduate School of Pharmaceutical Sciences, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C562353:2-(3-(3-benzamido-4-(benzylamino)-4-oxobutoxy)phenyl)cyclopropylamine; D000970:Antineoplastic Agents; D001549:Benzamides; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D056466:Histone Demethylases; C495195:KDM1A protein, human