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Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity
[Display omitted] As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphos...
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Published in: | Bioorganic & medicinal chemistry letters 2021-11, Vol.51, p.128361-128361, Article 128361 |
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As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered. |
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As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2021.128361</identifier><identifier>PMID: 34543755</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adenosine triphosphate ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Bilirubin ; Bilirubin - chemical synthesis ; Bilirubin - chemistry ; Bilirubin - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; P2X7R ; Purinergic P2X Receptor Antagonists - chemical synthesis ; Purinergic P2X Receptor Antagonists - chemistry ; Purinergic P2X Receptor Antagonists - pharmacology ; Receptors, Purinergic P2X7 - metabolism ; Structure-Activity Relationship ; Tumor</subject><ispartof>Bioorganic & medicinal chemistry letters, 2021-11, Vol.51, p.128361-128361, Article 128361</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-3649c512ad9d96fbb3b25f6140faa3a6efeeccbcbddef1292cfef120764d38193</citedby><cites>FETCH-LOGICAL-c356t-3649c512ad9d96fbb3b25f6140faa3a6efeeccbcbddef1292cfef120764d38193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34543755$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Yunshuo</creatorcontrib><creatorcontrib>Chen, Xiaotong</creatorcontrib><creatorcontrib>He, Chuanjie</creatorcontrib><creatorcontrib>Gao, Guanfei</creatorcontrib><creatorcontrib>Chen, Zhenzhen</creatorcontrib><creatorcontrib>Du, Jiangfeng</creatorcontrib><title>Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.</description><subject>Adenosine triphosphate</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Bilirubin</subject><subject>Bilirubin - chemical synthesis</subject><subject>Bilirubin - chemistry</subject><subject>Bilirubin - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>P2X7R</subject><subject>Purinergic P2X Receptor Antagonists - chemical synthesis</subject><subject>Purinergic P2X Receptor Antagonists - chemistry</subject><subject>Purinergic P2X Receptor Antagonists - pharmacology</subject><subject>Receptors, Purinergic P2X7 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kEtLAzEUhYMotlb_gAuZpZsZ854OuJH6hIIiCt2FJJNoyjxqkqn03zvDVJeuLvdyzuGeD4BzBDMEEb9aZ6rWVYYhRhnCc8LRAZgiymlKKGSHYAoLDtN5QVcTcBLCGkJEIaXHYEIooyRnbAqebl3Q7db4XdLaRLnK-U65JpEhafpzlbzgVf6ayCbKj7ZxISbfLn4Ou0tjV7c-kTq6rYu7U3BkZRXM2X7OwPv93dviMV0-PzwtbpapJozHlHBaaIawLIuy4FYpojCzvP_MSkkkN9YYrZVWZWkswgXWdpgw57Qkc1SQGbgccze-_epMiKLuK5iqko1puyAwyxnkeY7yXopHqfZtCN5YsfGuln4nEBQDQrEWA0IxIBQjwt50sc_vVG3KP8svs15wPQpM33LrjBdBO9NoUzpvdBRl6_7L_wFN1YLw</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Zhao, Yunshuo</creator><creator>Chen, Xiaotong</creator><creator>He, Chuanjie</creator><creator>Gao, Guanfei</creator><creator>Chen, Zhenzhen</creator><creator>Du, Jiangfeng</creator><general>Elsevier Ltd</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>7X8</scope></search><sort><creationdate>20211101</creationdate><title>Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity</title><author>Zhao, Yunshuo ; Chen, Xiaotong ; He, Chuanjie ; Gao, Guanfei ; Chen, Zhenzhen ; Du, Jiangfeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-3649c512ad9d96fbb3b25f6140faa3a6efeeccbcbddef1292cfef120764d38193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenosine triphosphate</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Bilirubin</topic><topic>Bilirubin - chemical synthesis</topic><topic>Bilirubin - chemistry</topic><topic>Bilirubin - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>P2X7R</topic><topic>Purinergic P2X Receptor Antagonists - chemical synthesis</topic><topic>Purinergic P2X Receptor Antagonists - chemistry</topic><topic>Purinergic P2X Receptor Antagonists - pharmacology</topic><topic>Receptors, Purinergic P2X7 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Yunshuo</creatorcontrib><creatorcontrib>Chen, Xiaotong</creatorcontrib><creatorcontrib>He, Chuanjie</creatorcontrib><creatorcontrib>Gao, Guanfei</creatorcontrib><creatorcontrib>Chen, Zhenzhen</creatorcontrib><creatorcontrib>Du, Jiangfeng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Yunshuo</au><au>Chen, Xiaotong</au><au>He, Chuanjie</au><au>Gao, Guanfei</au><au>Chen, Zhenzhen</au><au>Du, Jiangfeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2021-11-01</date><risdate>2021</risdate><volume>51</volume><spage>128361</spage><epage>128361</epage><pages>128361-128361</pages><artnum>128361</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3β were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34543755</pmid><doi>10.1016/j.bmcl.2021.128361</doi><tpages>1</tpages></addata></record> |
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subjects | Adenosine triphosphate Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Bilirubin Bilirubin - chemical synthesis Bilirubin - chemistry Bilirubin - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Discovery Drug Screening Assays, Antitumor Humans Molecular Structure P2X7R Purinergic P2X Receptor Antagonists - chemical synthesis Purinergic P2X Receptor Antagonists - chemistry Purinergic P2X Receptor Antagonists - pharmacology Receptors, Purinergic P2X7 - metabolism Structure-Activity Relationship Tumor |
title | Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity |
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