Identification of effective CCR2 inhibitors for cancer therapy using humanized mice
Abstract C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clini...
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| Veröffentlicht in: | Journal of biochemistry (Tokyo) 2024-02, Vol.175 (2), p.195-204 |
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| container_title | Journal of biochemistry (Tokyo) |
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| creator | Sugiyama, Shigeaki Yumimoto, Kanae Fujinuma, Shun Nakayama, Keiichi I |
| description | Abstract
C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.
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| doi_str_mv | 10.1093/jb/mvad086 |
| format | Article |
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C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0021-924X</identifier><identifier>EISSN: 1756-2651</identifier><identifier>DOI: 10.1093/jb/mvad086</identifier><identifier>PMID: 37947138</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Antagonists ; Calcium antagonists ; Calcium influx ; Cancer ; Cancer therapies ; CC chemokine receptors ; Chemokine receptors ; Chemokines ; Drug development ; Drug screening ; Effectiveness ; Experimental methods ; Inflammatory diseases ; Inhibitors ; Leukemia ; Lung cancer ; Lungs ; Metastases ; Metastasis ; Monocyte chemoattractant protein 1 ; Monocytes ; Monocytic leukemia ; Oral administration ; Suppressor cells</subject><ispartof>Journal of biochemistry (Tokyo), 2024-02, Vol.175 (2), p.195-204</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c367t-4faf51fc25525cba79f90b91c4e95a8ea982b5e183c7dbfdf7b440589601fe183</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37947138$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sugiyama, Shigeaki</creatorcontrib><creatorcontrib>Yumimoto, Kanae</creatorcontrib><creatorcontrib>Fujinuma, Shun</creatorcontrib><creatorcontrib>Nakayama, Keiichi I</creatorcontrib><title>Identification of effective CCR2 inhibitors for cancer therapy using humanized mice</title><title>Journal of biochemistry (Tokyo)</title><addtitle>J Biochem</addtitle><description>Abstract
C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.
Graphical Abstract
Graphical Abstract</description><subject>Antagonists</subject><subject>Calcium antagonists</subject><subject>Calcium influx</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>CC chemokine receptors</subject><subject>Chemokine receptors</subject><subject>Chemokines</subject><subject>Drug development</subject><subject>Drug screening</subject><subject>Effectiveness</subject><subject>Experimental methods</subject><subject>Inflammatory diseases</subject><subject>Inhibitors</subject><subject>Leukemia</subject><subject>Lung cancer</subject><subject>Lungs</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Monocytes</subject><subject>Monocytic leukemia</subject><subject>Oral administration</subject><subject>Suppressor cells</subject><issn>0021-924X</issn><issn>1756-2651</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp90FtLwzAYBuAgipuHG3-ABEQQoS5Jm7a5lOFhMBA8gHclSb-4lLWpSTuYv96OTS-88CokeXj5vhehM0puKBHxpFKTeiVLkqd7aEwznkYs5XQfjQlhNBIseR-hoxCqzZXF8SEaxZlIMhrnY_QyK6HprLFadtY12BkMxoDu7ArwdPrMsG0WVtnO-YCN81jLRoPH3QK8bNe4D7b5wIu-lo39ghLXVsMJOjByGeB0dx6jt_u71-ljNH96mE1v55GO06yLEiMNp0YzzhnXSmbCCKIE1QkILnOQImeKA81jnZXKlCZTSUJ4LlJCzeb5GF1tc1vvPnsIXVHboGG5lA24PhQsz4fl05jSgV78oZXrfTNMV2y-OSEpIYO63irtXQgeTNF6W0u_LigpNlUXlSp2VQ_4fBfZqxrKX_rT7QAut8D17X9B3_KBhrs</recordid><startdate>20240225</startdate><enddate>20240225</enddate><creator>Sugiyama, Shigeaki</creator><creator>Yumimoto, Kanae</creator><creator>Fujinuma, Shun</creator><creator>Nakayama, Keiichi I</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20240225</creationdate><title>Identification of effective CCR2 inhibitors for cancer therapy using humanized mice</title><author>Sugiyama, Shigeaki ; Yumimoto, Kanae ; Fujinuma, Shun ; Nakayama, Keiichi I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c367t-4faf51fc25525cba79f90b91c4e95a8ea982b5e183c7dbfdf7b440589601fe183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antagonists</topic><topic>Calcium antagonists</topic><topic>Calcium influx</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>CC chemokine receptors</topic><topic>Chemokine receptors</topic><topic>Chemokines</topic><topic>Drug development</topic><topic>Drug screening</topic><topic>Effectiveness</topic><topic>Experimental methods</topic><topic>Inflammatory diseases</topic><topic>Inhibitors</topic><topic>Leukemia</topic><topic>Lung cancer</topic><topic>Lungs</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Monocytes</topic><topic>Monocytic leukemia</topic><topic>Oral administration</topic><topic>Suppressor cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sugiyama, Shigeaki</creatorcontrib><creatorcontrib>Yumimoto, Kanae</creatorcontrib><creatorcontrib>Fujinuma, Shun</creatorcontrib><creatorcontrib>Nakayama, Keiichi I</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biochemistry (Tokyo)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sugiyama, Shigeaki</au><au>Yumimoto, Kanae</au><au>Fujinuma, Shun</au><au>Nakayama, Keiichi I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of effective CCR2 inhibitors for cancer therapy using humanized mice</atitle><jtitle>Journal of biochemistry (Tokyo)</jtitle><addtitle>J Biochem</addtitle><date>2024-02-25</date><risdate>2024</risdate><volume>175</volume><issue>2</issue><spage>195</spage><epage>204</epage><pages>195-204</pages><issn>0021-924X</issn><eissn>1756-2651</eissn><abstract>Abstract
C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>37947138</pmid><doi>10.1093/jb/mvad086</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of biochemistry (Tokyo), 2024-02, Vol.175 (2), p.195-204 |
| issn | 0021-924X 1756-2651 |
| language | eng |
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| source | Oxford University Press Journals All Titles (1996-Current) |
| subjects | Antagonists Calcium antagonists Calcium influx Cancer Cancer therapies CC chemokine receptors Chemokine receptors Chemokines Drug development Drug screening Effectiveness Experimental methods Inflammatory diseases Inhibitors Leukemia Lung cancer Lungs Metastases Metastasis Monocyte chemoattractant protein 1 Monocytes Monocytic leukemia Oral administration Suppressor cells |
| title | Identification of effective CCR2 inhibitors for cancer therapy using humanized mice |
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