Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells
Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here,...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2019-08, Vol.40 (8), p.1076-1084 |
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| creator | Cao, Yue-peng Sun, Jing-ya Li, Mei-qian Dong, Yu Zhang, Yuan-heng Yan, Jun Huang, Rui-min Yan, Xiang |
| description | Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here, we investigated whether G9a, one of the histone H3 methyltransferases, was associated with UBC development. We first analyzed clinical data from public databases and found that G9a was significantly overexpressed in UBC patients. The TCGA Provisional dataset showed that the average expression level of G9a in primary UBC samples (
n
= 408) was 1.6-fold as much as that in normal bladder samples (
n
= 19;
P
|
| doi_str_mv | 10.1038/s41401-018-0205-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6786297</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2267386875</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-f3704d2ae7fe70b25dc2ce4652a8f5b0b1293235a33a800e349474739d97b12f3</originalsourceid><addsrcrecordid>eNp1kU9rFTEUxYMotlY_gBsJuHHR0Zt_k8lGkIfWQmk3dh0ymUxfSiZ5JjNCv70ZplYtdHVDzu-e5HAQekvgIwHWfSqccCANkK4BCqIRz9AxkVw0kgr-vJ5bSRoOHTtCr0q5BWCUEfUSHTGQreg4PUb-PO5972efIk4jPlMG93fY4DKZEPCUgrNLcNhvVMqn-PpyBy2np_VuWKwr2BzSYU7Fl9Vgv0wm4j6YYXAZWxPtOlwI5TV6MZpQ3Jv7eYKuv339sfveXFydne--XDSWS5ibkUngAzVOjk5CT8VgqXW8FdR0o-ihJ1TVGMIwZjoAx7jikkumBiWrNrIT9HnzPSz95Abr4pxN0IfsJ5PvdDJe_69Ev9c36ZduZddSJavBh3uDnH4ursx68mWNYKJLS9GUUgWKU9pW9P0j9DYtOdZ4lWol69pOikqRjbI5lZLd-PAZAnotUm9F6lqkXovU6867f1M8bPxprgJ0A0qV4o3Lf59-2vU3PAenjQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2267386875</pqid></control><display><type>article</type><title>Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells</title><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Cao, Yue-peng ; Sun, Jing-ya ; Li, Mei-qian ; Dong, Yu ; Zhang, Yuan-heng ; Yan, Jun ; Huang, Rui-min ; Yan, Xiang</creator><creatorcontrib>Cao, Yue-peng ; Sun, Jing-ya ; Li, Mei-qian ; Dong, Yu ; Zhang, Yuan-heng ; Yan, Jun ; Huang, Rui-min ; Yan, Xiang</creatorcontrib><description>Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here, we investigated whether G9a, one of the histone H3 methyltransferases, was associated with UBC development. We first analyzed clinical data from public databases and found that G9a was significantly overexpressed in UBC patients. The TCGA Provisional dataset showed that the average expression level of G9a in primary UBC samples (
n
= 408) was 1.6-fold as much as that in normal bladder samples (
n
= 19;
P
< 0.001). Then we used small interfering RNA to knockdown G9a in human UBC T24 and J82 cell lines in vitro, and observed that the cell viability was significantly decreased and cell apoptosis induced. Next, we choosed UNC0642, a small molecule inhibitor targeting G9a, with low cytotoxicity, and excellent in vivo pharmacokinetic properties, to test its anticancer effects against UBC cells in vitro and in vivo. Treatment with UNC0642 dose-dependently decreased the viability of T24, J82, and 5637 cells with the IC
50
values of 9.85 ± 0.41, 13.15 ± 1.72, and 9.57 ± 0.37 μM, respectively. Furthermore, treatment with UNC0642 (1−20 μM) dose-dependently decreased the levels of histone H3K9me2, the downstream target of G9a, and increased apoptosis in T24 and J82 cells. In nude mice bearing J82 engrafts, administration of UNC0642 (5 mg/kg, every other day, i.p., for 6 times) exerted significant suppressive effect on tumor growth without loss of mouse body weight. Moreover, administration of UNC0642 significantly reduced Ki67 expression and increased the level of cleaved Caspase 3 and BIM protein in J82 xenografts evidenced by immunohistochemistry and western blot analysis, respectively. Taken together, our data demonstrated that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-018-0205-5</identifier><identifier>PMID: 30765842</identifier><language>eng</language><publisher>Singapore: Springer Singapore</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - physiology ; BIM protein ; Biomedical and Life Sciences ; Biomedicine ; Bladder cancer ; Body weight ; Cancer ; Cancer therapies ; Caspase ; Caspase-3 ; Cell Proliferation - physiology ; Cell Survival - drug effects ; Cell viability ; Chemotherapy ; Cisplatin ; Cytotoxicity ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Epigenetics ; Gemcitabine ; Gene Expression Regulation, Neoplastic - physiology ; Gene Knockdown Techniques ; Histocompatibility Antigens - genetics ; Histone H3 ; Histone-Lysine N-Methyltransferase - antagonists & inhibitors ; Histone-Lysine N-Methyltransferase - genetics ; Histones ; Humans ; Immunohistochemistry ; Immunology ; Internal Medicine ; Male ; Medical Microbiology ; Metastases ; Mice, Nude ; Pharmacology/Toxicology ; Quinazolines - pharmacology ; Quinazolines - therapeutic use ; siRNA ; Therapeutic applications ; Urinary bladder ; Urinary Bladder - pathology ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - pathology ; Vaccine ; Viability ; Xenografts</subject><ispartof>Acta pharmacologica Sinica, 2019-08, Vol.40 (8), p.1076-1084</ispartof><rights>CPS and SIMM 2019</rights><rights>2019© CPS and SIMM 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-f3704d2ae7fe70b25dc2ce4652a8f5b0b1293235a33a800e349474739d97b12f3</citedby><cites>FETCH-LOGICAL-c470t-f3704d2ae7fe70b25dc2ce4652a8f5b0b1293235a33a800e349474739d97b12f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786297/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786297/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30765842$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Yue-peng</creatorcontrib><creatorcontrib>Sun, Jing-ya</creatorcontrib><creatorcontrib>Li, Mei-qian</creatorcontrib><creatorcontrib>Dong, Yu</creatorcontrib><creatorcontrib>Zhang, Yuan-heng</creatorcontrib><creatorcontrib>Yan, Jun</creatorcontrib><creatorcontrib>Huang, Rui-min</creatorcontrib><creatorcontrib>Yan, Xiang</creatorcontrib><title>Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here, we investigated whether G9a, one of the histone H3 methyltransferases, was associated with UBC development. We first analyzed clinical data from public databases and found that G9a was significantly overexpressed in UBC patients. The TCGA Provisional dataset showed that the average expression level of G9a in primary UBC samples (
n
= 408) was 1.6-fold as much as that in normal bladder samples (
n
= 19;
P
< 0.001). Then we used small interfering RNA to knockdown G9a in human UBC T24 and J82 cell lines in vitro, and observed that the cell viability was significantly decreased and cell apoptosis induced. Next, we choosed UNC0642, a small molecule inhibitor targeting G9a, with low cytotoxicity, and excellent in vivo pharmacokinetic properties, to test its anticancer effects against UBC cells in vitro and in vivo. Treatment with UNC0642 dose-dependently decreased the viability of T24, J82, and 5637 cells with the IC
50
values of 9.85 ± 0.41, 13.15 ± 1.72, and 9.57 ± 0.37 μM, respectively. Furthermore, treatment with UNC0642 (1−20 μM) dose-dependently decreased the levels of histone H3K9me2, the downstream target of G9a, and increased apoptosis in T24 and J82 cells. In nude mice bearing J82 engrafts, administration of UNC0642 (5 mg/kg, every other day, i.p., for 6 times) exerted significant suppressive effect on tumor growth without loss of mouse body weight. Moreover, administration of UNC0642 significantly reduced Ki67 expression and increased the level of cleaved Caspase 3 and BIM protein in J82 xenografts evidenced by immunohistochemistry and western blot analysis, respectively. Taken together, our data demonstrated that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>BIM protein</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bladder cancer</subject><subject>Body weight</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cell Proliferation - physiology</subject><subject>Cell Survival - drug effects</subject><subject>Cell viability</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cytotoxicity</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Epigenetics</subject><subject>Gemcitabine</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Gene Knockdown Techniques</subject><subject>Histocompatibility Antigens - genetics</subject><subject>Histone H3</subject><subject>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</subject><subject>Histone-Lysine N-Methyltransferase - genetics</subject><subject>Histones</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Metastases</subject><subject>Mice, Nude</subject><subject>Pharmacology/Toxicology</subject><subject>Quinazolines - pharmacology</subject><subject>Quinazolines - therapeutic use</subject><subject>siRNA</subject><subject>Therapeutic applications</subject><subject>Urinary bladder</subject><subject>Urinary Bladder - pathology</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><subject>Urinary Bladder Neoplasms - pathology</subject><subject>Vaccine</subject><subject>Viability</subject><subject>Xenografts</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU9rFTEUxYMotlY_gBsJuHHR0Zt_k8lGkIfWQmk3dh0ymUxfSiZ5JjNCv70ZplYtdHVDzu-e5HAQekvgIwHWfSqccCANkK4BCqIRz9AxkVw0kgr-vJ5bSRoOHTtCr0q5BWCUEfUSHTGQreg4PUb-PO5972efIk4jPlMG93fY4DKZEPCUgrNLcNhvVMqn-PpyBy2np_VuWKwr2BzSYU7Fl9Vgv0wm4j6YYXAZWxPtOlwI5TV6MZpQ3Jv7eYKuv339sfveXFydne--XDSWS5ibkUngAzVOjk5CT8VgqXW8FdR0o-ihJ1TVGMIwZjoAx7jikkumBiWrNrIT9HnzPSz95Abr4pxN0IfsJ5PvdDJe_69Ev9c36ZduZddSJavBh3uDnH4ursx68mWNYKJLS9GUUgWKU9pW9P0j9DYtOdZ4lWol69pOikqRjbI5lZLd-PAZAnotUm9F6lqkXovU6867f1M8bPxprgJ0A0qV4o3Lf59-2vU3PAenjQ</recordid><startdate>20190801</startdate><enddate>20190801</enddate><creator>Cao, Yue-peng</creator><creator>Sun, Jing-ya</creator><creator>Li, Mei-qian</creator><creator>Dong, Yu</creator><creator>Zhang, Yuan-heng</creator><creator>Yan, Jun</creator><creator>Huang, Rui-min</creator><creator>Yan, Xiang</creator><general>Springer Singapore</general><general>Nature Publishing Group</general><general>Nature Publishing Group UK</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190801</creationdate><title>Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells</title><author>Cao, Yue-peng ; Sun, Jing-ya ; Li, Mei-qian ; Dong, Yu ; Zhang, Yuan-heng ; Yan, Jun ; Huang, Rui-min ; Yan, Xiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-f3704d2ae7fe70b25dc2ce4652a8f5b0b1293235a33a800e349474739d97b12f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>BIM protein</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bladder cancer</topic><topic>Body weight</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Caspase</topic><topic>Caspase-3</topic><topic>Cell Proliferation - physiology</topic><topic>Cell Survival - drug effects</topic><topic>Cell viability</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Cytotoxicity</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Epigenetics</topic><topic>Gemcitabine</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Gene Knockdown Techniques</topic><topic>Histocompatibility Antigens - genetics</topic><topic>Histone H3</topic><topic>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</topic><topic>Histone-Lysine N-Methyltransferase - genetics</topic><topic>Histones</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Metastases</topic><topic>Mice, Nude</topic><topic>Pharmacology/Toxicology</topic><topic>Quinazolines - pharmacology</topic><topic>Quinazolines - therapeutic use</topic><topic>siRNA</topic><topic>Therapeutic applications</topic><topic>Urinary bladder</topic><topic>Urinary Bladder - pathology</topic><topic>Urinary Bladder Neoplasms - drug therapy</topic><topic>Urinary Bladder Neoplasms - pathology</topic><topic>Vaccine</topic><topic>Viability</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Yue-peng</creatorcontrib><creatorcontrib>Sun, Jing-ya</creatorcontrib><creatorcontrib>Li, Mei-qian</creatorcontrib><creatorcontrib>Dong, Yu</creatorcontrib><creatorcontrib>Zhang, Yuan-heng</creatorcontrib><creatorcontrib>Yan, Jun</creatorcontrib><creatorcontrib>Huang, Rui-min</creatorcontrib><creatorcontrib>Yan, Xiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Yue-peng</au><au>Sun, Jing-ya</au><au>Li, Mei-qian</au><au>Dong, Yu</au><au>Zhang, Yuan-heng</au><au>Yan, Jun</au><au>Huang, Rui-min</au><au>Yan, Xiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2019-08-01</date><risdate>2019</risdate><volume>40</volume><issue>8</issue><spage>1076</spage><epage>1084</epage><pages>1076-1084</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here, we investigated whether G9a, one of the histone H3 methyltransferases, was associated with UBC development. We first analyzed clinical data from public databases and found that G9a was significantly overexpressed in UBC patients. The TCGA Provisional dataset showed that the average expression level of G9a in primary UBC samples (
n
= 408) was 1.6-fold as much as that in normal bladder samples (
n
= 19;
P
< 0.001). Then we used small interfering RNA to knockdown G9a in human UBC T24 and J82 cell lines in vitro, and observed that the cell viability was significantly decreased and cell apoptosis induced. Next, we choosed UNC0642, a small molecule inhibitor targeting G9a, with low cytotoxicity, and excellent in vivo pharmacokinetic properties, to test its anticancer effects against UBC cells in vitro and in vivo. Treatment with UNC0642 dose-dependently decreased the viability of T24, J82, and 5637 cells with the IC
50
values of 9.85 ± 0.41, 13.15 ± 1.72, and 9.57 ± 0.37 μM, respectively. Furthermore, treatment with UNC0642 (1−20 μM) dose-dependently decreased the levels of histone H3K9me2, the downstream target of G9a, and increased apoptosis in T24 and J82 cells. In nude mice bearing J82 engrafts, administration of UNC0642 (5 mg/kg, every other day, i.p., for 6 times) exerted significant suppressive effect on tumor growth without loss of mouse body weight. Moreover, administration of UNC0642 significantly reduced Ki67 expression and increased the level of cleaved Caspase 3 and BIM protein in J82 xenografts evidenced by immunohistochemistry and western blot analysis, respectively. Taken together, our data demonstrated that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.</abstract><cop>Singapore</cop><pub>Springer Singapore</pub><pmid>30765842</pmid><doi>10.1038/s41401-018-0205-5</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Apoptosis - drug effects Apoptosis - physiology BIM protein Biomedical and Life Sciences Biomedicine Bladder cancer Body weight Cancer Cancer therapies Caspase Caspase-3 Cell Proliferation - physiology Cell Survival - drug effects Cell viability Chemotherapy Cisplatin Cytotoxicity Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Epigenetics Gemcitabine Gene Expression Regulation, Neoplastic - physiology Gene Knockdown Techniques Histocompatibility Antigens - genetics Histone H3 Histone-Lysine N-Methyltransferase - antagonists & inhibitors Histone-Lysine N-Methyltransferase - genetics Histones Humans Immunohistochemistry Immunology Internal Medicine Male Medical Microbiology Metastases Mice, Nude Pharmacology/Toxicology Quinazolines - pharmacology Quinazolines - therapeutic use siRNA Therapeutic applications Urinary bladder Urinary Bladder - pathology Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - pathology Vaccine Viability Xenografts |
| title | Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells |
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