MP29-09 NOVEL SELECTIVE LYSINE SPECIFIC DEMETHYLASE 1 INHIBITORS EFFECTIVELY IMPAIR CASTRATION RESISTANT PROSTATE CANCER GROWTH

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2018MP29-09 NOVEL SELECTIVE LYSINE SPECIFIC DEMETHYLASE 1 INHIBITORS EFFECTIVELY IMPAIR CASTRATION RESISTANT PROSTATE CANCER GROWTH Toshiki Etani, Taku Naiki, Takashi Nagai, Keitaro Iida, Ryosuke Ando, Noriyasu Kawai, Keiichi Tozawa, Takayoshi Suzuki, and Takahiro Yasui Toshiki EtaniToshiki Etani More articles by this author , Taku NaikiTaku Naiki More articles by this author , Takashi NagaiTakashi Nagai More articles by this author , Keitaro IidaKeitaro Iida More articles by this author , Ryosuke AndoRyosuke Ando More articles by this author , Noriyasu KawaiNoriyasu Kawai More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , Takayoshi SuzukiTakayoshi Suzuki More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.929AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lysine-specific demethylase 1 (LSD1), the first-identified histone demethylase, is a novel target for prostate cancer therapy. We examined the anticancer effects of NCL1 and NCD38, selective inhibitors of LSD1 (LSD1i) that were first discovered at our university. METHODS Various tests using LNCaP (a hormone-sensitive prostate cancer cell line) and PCai1 (a castration-resistant prostate cancer [CRPC] cell line established in our institute), PC3 and 22Rv1 (CRPC cell line) cells were used to confirm the anticancer effects of NCL1 and NCD38. Cell viability was assessed by performing a WST assay. Invasion and migration assay were also performed to assess the status of cell invasion and cell migration. For autophagy analysis, cells were incubated with or without chloroquine (CQ) in the presence or absence of LSD1i. Subsequently, transmission electron microscopy (TEM), fluorescent immunocytochemistry, and WST assay were performed with the treated and non-treated cells. A combination index analysis was performed to assess the effects of LSD1i and CQ. Finally, the effect on xenograft tumors in CRPC mice models was measured by subcutaneously injecting castrated nude mice with PCai1 cells. Mice were injected intraperitoneally with LSD1i or the vehicle, and their subsequent growth was recorded. RESULTS The WST assay revealed reduced number of viable cells after LSD1i treatment. A dose-dependent induction of apoptosis by LSD1i was noted using flow cytometry. LSD1i inhibited invasion and migration. Autophagosomes were observed in the LNCaP cells treated with NCL1. The expression level of LC3-II was significantly increased in the cells treated with LSD1i and CQ. Moreover, the combination of NCL1 and CQ significantly decreased cell growth in vitro; however, it had no synergistic effect in vivo. Xenograft tumor volume was reduced in the NCL1 and NCD38-treated mice compared to the controls; no adverse effects were observed. CONCLUSIONS Castration-resistant prostate cancer growth was effectively suppressed with NCL1 and NCD38 both, in vitro and in vivo, without any adverse events via apoptosis regulation and autophagy, indicating the potential use of LSD1 inhibitors as therapeutic agents for prostate cancer. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e369 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Toshiki Etani More articles by this author Taku Naiki More articles by this author Takashi Nagai More articles by this author Keitaro Iida More articles by this author Ryosuke Ando More articles by this author Noriyasu Kawai More articles by this author Keiichi Tozawa More articles by this author Takayoshi Suzuki More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...