NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy
Identifieur interne : 000560 ( Pmc/Checkpoint ); précédent : 000559; suivant : 000561NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy
Auteurs : Toshiki Etani ; Taku Naiki ; Aya Naiki-Ito ; Takayoshi Suzuki [Japon] ; Keitaro Iida ; Satoshi Nozaki ; Hiroyuki Kato ; Yuko Nagayasu ; Shugo Suzuki ; Noriyasu Kawai ; Takahiro Yasui ; Satoru TakahashiSource :
- Journal of Clinical Medicine [ 2077-0383 ] ; 2019.
Abstract
Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.
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DOI: 10.3390/jcm8040442
PubMed: 30935141
PubMed Central: 6517972
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy</title><author><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name><affiliation><nlm:aff id="af3-jcm-08-00442">Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 606-0823, Japan;<email>suzukit@koto.kpu-m.ac.jp</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-jcm-08-00442">CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015</wicri:regionArea><wicri:noRegion>Kawaguchi 332-0015</wicri:noRegion></affiliation></author><author><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30935141</idno><idno type="pmc">6517972</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517972</idno><idno type="RBID">PMC:6517972</idno><idno type="doi">10.3390/jcm8040442</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000663</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000663</idno><idno type="wicri:Area/Pmc/Curation">000663</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000663</idno><idno type="wicri:Area/Pmc/Checkpoint">000560</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000560</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy</title><author><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name><affiliation><nlm:aff id="af3-jcm-08-00442">Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 606-0823, Japan;<email>suzukit@koto.kpu-m.ac.jp</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-jcm-08-00442">CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015</wicri:regionArea><wicri:noRegion>Kawaguchi 332-0015</wicri:noRegion></affiliation></author><author><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Clinical Medicine</title><idno type="eISSN">2077-0383</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Frydenberg, M" uniqKey="Frydenberg M">M. Frydenberg</name></author><author><name sortKey="Stricker, P D" uniqKey="Stricker P">P.D. Stricker</name></author><author><name sortKey="Kaye, K W" uniqKey="Kaye K">K.W. Kaye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Bono, J S" uniqKey="De Bono J">J.S. de Bono</name></author><author><name sortKey="Logothetis, C J" uniqKey="Logothetis C">C.J. Logothetis</name></author><author><name sortKey="Molina, A" uniqKey="Molina A">A. Molina</name></author><author><name sortKey="Fizazi, K" uniqKey="Fizazi K">K. Fizazi</name></author><author><name sortKey="North, S" uniqKey="North S">S. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Med</journal-id><journal-id journal-id-type="iso-abbrev">J Clin Med</journal-id><journal-id journal-id-type="publisher-id">jcm</journal-id><journal-title-group><journal-title>Journal of Clinical Medicine</journal-title></journal-title-group><issn pub-type="epub">2077-0383</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30935141</article-id><article-id pub-id-type="pmc">6517972</article-id><article-id pub-id-type="doi">10.3390/jcm8040442</article-id><article-id pub-id-type="publisher-id">jcm-08-00442</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Etani</surname><given-names>Toshiki</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7638-6048</contrib-id><name><surname>Naiki</surname><given-names>Taku</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref><xref rid="c1-jcm-08-00442" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-0828-2033</contrib-id><name><surname>Naiki-Ito</surname><given-names>Aya</given-names></name><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-2439-879X</contrib-id><name><surname>Suzuki</surname><given-names>Takayoshi</given-names></name><xref ref-type="aff" rid="af3-jcm-08-00442">3</xref><xref ref-type="aff" rid="af4-jcm-08-00442">4</xref></contrib><contrib contrib-type="author"><name><surname>Iida</surname><given-names>Keitaro</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref></contrib><contrib contrib-type="author"><name><surname>Nozaki</surname><given-names>Satoshi</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref></contrib><contrib contrib-type="author"><name><surname>Kato</surname><given-names>Hiroyuki</given-names></name><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref></contrib><contrib contrib-type="author"><name><surname>Nagayasu</surname><given-names>Yuko</given-names></name><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref></contrib><contrib contrib-type="author"><name><surname>Suzuki</surname><given-names>Shugo</given-names></name><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref></contrib><contrib contrib-type="author"><name><surname>Kawai</surname><given-names>Noriyasu</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-2197-2477</contrib-id><name><surname>Yasui</surname><given-names>Takahiro</given-names></name><xref ref-type="aff" rid="af1-jcm-08-00442">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8139-8158</contrib-id><name><surname>Takahashi</surname><given-names>Satoru</given-names></name><xref ref-type="aff" rid="af2-jcm-08-00442">2</xref></contrib></contrib-group><aff id="af1-jcm-08-00442"><label>1</label>Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</aff><aff id="af2-jcm-08-00442"><label>2</label>Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</aff><aff id="af3-jcm-08-00442"><label>3</label>Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 606-0823, Japan;<email>suzukit@koto.kpu-m.ac.jp</email></aff><aff id="af4-jcm-08-00442"><label>4</label>CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015, Japan</aff><author-notes><corresp id="c1-jcm-08-00442"><label>*</label>Correspondence: <email>naiki@med.nagoya-cu.ac.jp</email>; Tel.: +81-52-853-8266; Fax: +81-52-853-3179</corresp></author-notes><pub-date pub-type="epub"><day>31</day><month>3</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>4</month><year>2019</year></pub-date><volume>8</volume><issue>4</issue><elocation-id>442</elocation-id><history><date date-type="received"><day>12</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>27</day><month>3</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.</p></abstract><kwd-group><kwd>LSD1</kwd><kwd>epigenetics</kwd><kwd>castration-resistant prostate cancer</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="jcm-08-00442-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>(<bold>A</bold>–<bold>F</bold>) Hematoxylin and eosin (HE) staining (<bold>A</bold>), and immunohistochemistry for Nkx3.1, a sensitive specific marker of differentiated adenocarcinoma originating from the prostate (<bold>B</bold>), and histone lysine demethylase 1 (LSD1) (<bold>C</bold>) of castration-naïve prostate cancer (castration-naïve PC) specimens obtained by prostate biopsy for an initial diagnosis in patients. HE staining (<bold>D</bold>), and immunohistochemistry for Nkx3.1 (<bold>E</bold>), and LSD1 (<bold>F</bold>) of castration-resistant prostate cancer (CRPC) specimens obtained by prostate biopsy after the acquisition of castration resistance and treatment with androgen deprivation therapy. Nuclei were counterstained with hematoxylin. Scale bar is 50 μm. (<bold>G</bold>–<bold>J</bold>) HE staining (<bold>G</bold>), and immunohistochemistry for Nkx3.1 (<bold>H</bold>), LSD1 (<bold>I</bold>), and synaptophysin (<bold>J</bold>) in prostate biopsy specimens obtained after the acquisition of castration resistance and neuroendocrine differentiation after treatment with androgen deprivation therapy. Scale bar is 50 μm. (<bold>K</bold>) A graphical comparison of intensity levels of LSD1 expression between castration-naïve PC and CRPC biopsy samples. n.s.: not significant.</p></caption><graphic xlink:href="jcm-08-00442-g001"></graphic></fig><fig id="jcm-08-00442-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>(<bold>A</bold>) Chromatin immunoprecipitation (ChIP) analysis in 22Rv1 cells using a histone H3 lysine 4 dimethylation (H3K4me2) antibody showed that NCL1 induced the attenuation of demethylation of H3K4me2 in the promoter regions of P21. Western blot analysis of P21 in 22Rv1 cells is shown. The protein expression of P21 was increased, reflecting the results of the ChIP analysis. β-actin was used as an internal loading control. (<bold>B</bold>) Western blot analysis of PCai1CS, 22Rv1, and PC3 cells for LSD1. All castration-resistant prostate cancer (CRPC) cell lines expressed LSD1. β-actin was used as an internal loading control. (<bold>C</bold>) PCai1CS and 22Rv1 cells were treated with vehicle (control) or NCL1, and subjected to WST-8 assay to measure cell proliferation. NCL1 treatment reduced the cell viability of the two CRPC cell lines in a dose-dependent manner. (<bold>D</bold>) Western blot analyses 48 h after NCL1 treatment of 22Rv1, PCai1CS, and PC3 cells. The cell cycle-related protein expression of cyclin B1, cyclin D1, CDK2, CDK4, and p27<sup>KIP</sup> were unchanged. Treatment with NCL1 resulted in a marked elevation in cleaved caspase 3 without any change in caspase 3. In addition, protein expression of microtubule-associated protein light chain 3 (LC3)-II was elevated in NCL1-treated CRPC cells. β-actin was used as an internal loading control. (<bold>E</bold>) Guava<sup>®</sup> apoptosis analysis of PC3 and 22Rv1 cells. NCL1, the autophagy inhibitor chloroquine (CQ), and a combination of these drugs induced apoptosis in CRPC cells. Mean ± standard deviation (SD); * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.001, *** <italic>p</italic> < 0.0001.</p></caption><graphic xlink:href="jcm-08-00442-g002"></graphic></fig><fig id="jcm-08-00442-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>(<bold>A</bold>–<bold>D</bold>) Detection of the activation of lysosomes using LysoTracker analysis in 22Rv1 cells. Cells were treated with vehicle control (<bold>A</bold>), 50 μM NCL1 (<bold>B</bold>), 50 μM chloroquine (CQ) (<bold>C</bold>), or with 50 μM NCL1 and 50 μM CQ (<bold>D</bold>). Blue: nuclei, red: lysosomes. (<bold>E</bold>) 22Rv1 cells were treated with 50 μM NCL1 and/or 50 μM CQ. A WST-8 assay, in which the dye absorption rate positively correlated with cell viability, revealed that a combination of NCL1 and CQ decreased cell growth. (<bold>F</bold>) A combination index was calculated from the results of the WST-8 assay in <xref ref-type="fig" rid="jcm-08-00442-f003">Figure 3</xref>E. The combination of NCL1 and CQ showed a synergistic effect. (<bold>G</bold>) Cells were treated with 50 μM NCL1 for 3 h, 12 h, and 72 h. Three hours after NCL1 treatment, the formation of autophagosomes was noted by transmission electron microscopy (TEM). The cytoplasm also showed increased numbers of structures (visible in the 72 h figure) from 24 h to 72 h. Scale bar is 20 μm.</p></caption><graphic xlink:href="jcm-08-00442-g003"></graphic></fig><fig id="jcm-08-00442-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>(<bold>A</bold>) Tumor growth was significantly inhibited in mice treated with 1.0 mg/kg NCL1 as compared to vehicle controls. (<bold>B</bold>) A terminal deoxy nucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed in NCL1-treated and control mice, and quantified as the mean TUNEL labeling percentage based on at least five randomly selected high-power microscope fields per individual. (<bold>C</bold>) Immunohistochemistry for CD31. Positivity was quantified as the mean number of vessels/mm<sup>2</sup> based on at least five randomly selected high-power microscopic fields per individual. (<bold>D</bold>,<bold>E</bold>) Representative immunohistochemistry of LSD1 in a subcutaneous PCai1 tumor. Uncastrated tumor (<bold>D</bold>), and 1 week after castration (<bold>E</bold>). Scale bar is 50 μm. (<bold>F</bold>,<bold>G</bold>) Hematoxylin and eosin (HE) staining in subcutaneous tumors from vehicle control (<bold>F</bold>) and 1.0 mg/kg NCL1-treated (<bold>G</bold>) mice. Vacuolation (black arrowheads) was increased in the NCL1-treated group compared with controls. Scale bar is 50 μm. (<bold>H</bold>,<bold>I</bold>) TUNEL staining for apoptosis in subcutaneous tumors from vehicle control (<bold>H</bold>) and 1.0 mg/kg NCL1-treated (<bold>I</bold>) mice. White arrowheads indicate TUNEL-positive cells. Scale bar is 50 μm. (<bold>J</bold>,<bold>K</bold>) Representative immunohistochemical images of CD31 in subcutaneous tumors from control (<bold>J</bold>) and 1.0 mg/kg NCL1-treated (<bold>K</bold>) mice. Black arrowheads indicate CD31-positive cells. Scale bar is 50 μm. Mean ± standard deviation (SD); * <italic>p</italic> < 0.05.</p></caption><graphic xlink:href="jcm-08-00442-g004"></graphic></fig><table-wrap id="jcm-08-00442-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">jcm-08-00442-t001_Table 1</object-id><label>Table 1</label><caption><p>Relative organ weights at the experiment’s termination in a PCai1 mouse tumor model. BW: body weight; R: right; L: left.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">No. of Mice</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">BW (g)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Liver (%)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">R-Kidney (%)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">L-Kidney (%)</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Control</td><td align="center" valign="middle" rowspan="1" colspan="1">11</td><td align="center" valign="middle" rowspan="1" colspan="1">23.4 ± 1.3</td><td align="center" valign="middle" rowspan="1" colspan="1">5.14 ± 0.22</td><td align="center" valign="middle" rowspan="1" colspan="1">0.78 ± 0.02</td><td align="center" valign="middle" rowspan="1" colspan="1">0.80 ± 0.05</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCL1 1.0 mg/kg</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">23.5 ± 1.5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.30 ± 0.26</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.81 ± 0.03</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.82 ± 0.04</td></tr></tbody></table></table-wrap><table-wrap id="jcm-08-00442-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">jcm-08-00442-t002_Table 2</object-id><label>Table 2</label><caption><p>Blood results at the experiment’s termination in a PCai1mouse tumor model. AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; T-Bil: total bilirubin; T-Chol: total cholesterol; Crea: creatinine; BUN: blood urea nitrogen; Na: sodium; K: potassium; Cl: chloride; Ca: calcium. Mean ± standard deviation (SD).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Control</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">NCL1 1.0 mg/kg</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">AST</td><td align="center" valign="middle" rowspan="1" colspan="1">56.2 ± 10.3</td><td align="center" valign="middle" rowspan="1" colspan="1">55.9 ± 10.6</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">ALT</td><td align="center" valign="middle" rowspan="1" colspan="1">28.2 ± 6.3</td><td align="center" valign="middle" rowspan="1" colspan="1">27.1 ± 3.6</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">ALP</td><td align="center" valign="middle" rowspan="1" colspan="1">240.7 ± 20.6</td><td align="center" valign="middle" rowspan="1" colspan="1">250.2 ± 30.9</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">T-Bil</td><td align="center" valign="middle" rowspan="1" colspan="1">0.04 ± 0.01</td><td align="center" valign="middle" rowspan="1" colspan="1">0.04 ± 0.01</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">T-Chol</td><td align="center" valign="middle" rowspan="1" colspan="1">83.5 ± 8.3</td><td align="center" valign="middle" rowspan="1" colspan="1">85.1 ± 8.3</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Crea</td><td align="center" valign="middle" rowspan="1" colspan="1">0.09 ± 0.01</td><td align="center" valign="middle" rowspan="1" colspan="1">0.10 ± 0.01</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">BUN</td><td align="center" valign="middle" rowspan="1" colspan="1">23.4 ± 3.2</td><td align="center" valign="middle" rowspan="1" colspan="1">23.5 ± 2.7</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Na</td><td align="center" valign="middle" rowspan="1" colspan="1">146.3 ± 3.8</td><td align="center" valign="middle" rowspan="1" colspan="1">146.8 ± 2.7</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">K</td><td align="center" valign="middle" rowspan="1" colspan="1">6.7 ± 1.0</td><td align="center" valign="middle" rowspan="1" colspan="1">5.9 ± 0.7</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Cl</td><td align="center" valign="middle" rowspan="1" colspan="1">110.4 ± 6.5</td><td align="center" valign="middle" rowspan="1" colspan="1">109.7 ± 5.3</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ca</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.5 ± 0.2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.4 ± 0.3</td></tr></tbody></table></table-wrap></floats-group></pmc><affiliations><list><country><li>Japon</li></country></list><tree><noCountry><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name></noCountry><country name="Japon"><noRegion><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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