Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7
The P2X7 receptor is not only involved in cell proliferation, but also acts as an adenosine 5′-triphosphate (ATP)-gated non-selective channel, and its expression is increased in human melanoma. An irreversible antagonist of P2X7, such as oxidized ATP (oxATP), might block P2X7 receptor-mediated ATP r...
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| Veröffentlicht in: | European journal of pharmacology 2012-11, Vol.695 (1-3), p.20-26 |
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| creator | Hattori, Fumie Ohshima, Yasuhiro Seki, Shizuka Tsukimoto, Mitsutoshi Sato, Mitsuru Takenouchi, Takato Suzuki, Akina Takai, Erina Kitani, Hiroshi Harada, Hitoshi Kojima, Shuji |
| description | The P2X7 receptor is not only involved in cell proliferation, but also acts as an adenosine 5′-triphosphate (ATP)-gated non-selective channel, and its expression is increased in human melanoma. An irreversible antagonist of P2X7, such as oxidized ATP (oxATP), might block P2X7 receptor-mediated ATP release and proliferative signaling. Therefore, we carried out basic studies to test this idea and to examine the feasibility of using oxATP to treat B16 melanoma.
We first found that low-pH conditions (mimicking the hypoxia and acidosis commonly seen in solid tumors) induced P2X7 receptor-mediated ATP release from B16 melanoma cells. Then, we compared the proliferation rates of B16 melanoma wild-type cells and B16 P2X7 receptor-knockdown clone (P2X7-KDC) cells in the presence of P2X7 agonists. The proliferation rate, as well as the ATP release, of agonist-treated P2X7-KDC cells was lower than that of agonist-treated wild-type cells. Next, the effect of P2X7 antagonist oxATP on B16 melanoma cell growth was examined in vitro and in vivo. oxATP significantly decreased B16 melanoma cell proliferation in vitro, and also significantly inhibited tumor growth in B16 melanoma-bearing mice.
These data indicate that extracellularly released ATP may serve as an intercellular signaling molecule. We propose that the P2X7 receptor is a promising target for treatment of solid tumors. |
| doi_str_mv | 10.1016/j.ejphar.2012.09.001 |
| format | Article |
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We first found that low-pH conditions (mimicking the hypoxia and acidosis commonly seen in solid tumors) induced P2X7 receptor-mediated ATP release from B16 melanoma cells. Then, we compared the proliferation rates of B16 melanoma wild-type cells and B16 P2X7 receptor-knockdown clone (P2X7-KDC) cells in the presence of P2X7 agonists. The proliferation rate, as well as the ATP release, of agonist-treated P2X7-KDC cells was lower than that of agonist-treated wild-type cells. Next, the effect of P2X7 antagonist oxATP on B16 melanoma cell growth was examined in vitro and in vivo. oxATP significantly decreased B16 melanoma cell proliferation in vitro, and also significantly inhibited tumor growth in B16 melanoma-bearing mice.
These data indicate that extracellularly released ATP may serve as an intercellular signaling molecule. We propose that the P2X7 receptor is a promising target for treatment of solid tumors.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2012.09.001</identifier><identifier>PMID: 22981895</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>acidosis ; adenosine ; adenosine triphosphate ; Adenosine Triphosphate - analogs & derivatives ; Adenosine Triphosphate - pharmacology ; Adenosine Triphosphate - secretion ; Adenosine Triphosphate - therapeutic use ; agonists ; Animals ; antagonists ; cell growth ; cell proliferation ; Cell Proliferation - drug effects ; Feasibility Studies ; Gene Knockdown Techniques ; humans ; Hydrogen-Ion Concentration ; hypoxia ; Inhibition ; Male ; melanoma ; Melanoma, Experimental - drug therapy ; Melanoma, Experimental - metabolism ; Melanoma, Experimental - pathology ; Mice ; Mice, Inbred C57BL ; Molecular Targeted Therapy - methods ; Oxidized ATP ; P2X7 ; pharmacology ; Purinergic P2X Receptor Antagonists - pharmacology ; Purinergic P2X Receptor Antagonists - therapeutic use ; Purinergic receptor ; Receptors, Purinergic P2X7 - deficiency ; Receptors, Purinergic P2X7 - genetics ; Receptors, Purinergic P2X7 - metabolism ; Signal Transduction - drug effects ; therapeutics ; Tumor growth</subject><ispartof>European journal of pharmacology, 2012-11, Vol.695 (1-3), p.20-26</ispartof><rights>2012 Elsevier B.V.</rights><rights>Copyright © 2012 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-3e88439567146ef38c1b1798e983a6e57a7426efa4c464c07ee5ed77fa18e1983</citedby><cites>FETCH-LOGICAL-c498t-3e88439567146ef38c1b1798e983a6e57a7426efa4c464c07ee5ed77fa18e1983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejphar.2012.09.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27926,27927,45997</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22981895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hattori, Fumie</creatorcontrib><creatorcontrib>Ohshima, Yasuhiro</creatorcontrib><creatorcontrib>Seki, Shizuka</creatorcontrib><creatorcontrib>Tsukimoto, Mitsutoshi</creatorcontrib><creatorcontrib>Sato, Mitsuru</creatorcontrib><creatorcontrib>Takenouchi, Takato</creatorcontrib><creatorcontrib>Suzuki, Akina</creatorcontrib><creatorcontrib>Takai, Erina</creatorcontrib><creatorcontrib>Kitani, Hiroshi</creatorcontrib><creatorcontrib>Harada, Hitoshi</creatorcontrib><creatorcontrib>Kojima, Shuji</creatorcontrib><title>Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>The P2X7 receptor is not only involved in cell proliferation, but also acts as an adenosine 5′-triphosphate (ATP)-gated non-selective channel, and its expression is increased in human melanoma. An irreversible antagonist of P2X7, such as oxidized ATP (oxATP), might block P2X7 receptor-mediated ATP release and proliferative signaling. Therefore, we carried out basic studies to test this idea and to examine the feasibility of using oxATP to treat B16 melanoma.
We first found that low-pH conditions (mimicking the hypoxia and acidosis commonly seen in solid tumors) induced P2X7 receptor-mediated ATP release from B16 melanoma cells. Then, we compared the proliferation rates of B16 melanoma wild-type cells and B16 P2X7 receptor-knockdown clone (P2X7-KDC) cells in the presence of P2X7 agonists. The proliferation rate, as well as the ATP release, of agonist-treated P2X7-KDC cells was lower than that of agonist-treated wild-type cells. Next, the effect of P2X7 antagonist oxATP on B16 melanoma cell growth was examined in vitro and in vivo. oxATP significantly decreased B16 melanoma cell proliferation in vitro, and also significantly inhibited tumor growth in B16 melanoma-bearing mice.
These data indicate that extracellularly released ATP may serve as an intercellular signaling molecule. We propose that the P2X7 receptor is a promising target for treatment of solid tumors.</description><subject>acidosis</subject><subject>adenosine</subject><subject>adenosine triphosphate</subject><subject>Adenosine Triphosphate - analogs & derivatives</subject><subject>Adenosine Triphosphate - pharmacology</subject><subject>Adenosine Triphosphate - secretion</subject><subject>Adenosine Triphosphate - therapeutic use</subject><subject>agonists</subject><subject>Animals</subject><subject>antagonists</subject><subject>cell growth</subject><subject>cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Feasibility Studies</subject><subject>Gene Knockdown Techniques</subject><subject>humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>hypoxia</subject><subject>Inhibition</subject><subject>Male</subject><subject>melanoma</subject><subject>Melanoma, Experimental - drug therapy</subject><subject>Melanoma, Experimental - metabolism</subject><subject>Melanoma, Experimental - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Targeted Therapy - methods</subject><subject>Oxidized ATP</subject><subject>P2X7</subject><subject>pharmacology</subject><subject>Purinergic P2X Receptor Antagonists - pharmacology</subject><subject>Purinergic P2X Receptor Antagonists - therapeutic use</subject><subject>Purinergic receptor</subject><subject>Receptors, Purinergic P2X7 - deficiency</subject><subject>Receptors, Purinergic P2X7 - genetics</subject><subject>Receptors, Purinergic P2X7 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>therapeutics</subject><subject>Tumor growth</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1P3DAQQK2qVdlS_gGiPvaS1ON1YvtSCRAUJKQiFSRulteZLF5t1qntVCy_HqPQHnsaaebN1yPkGFgNDNpvmxo346ONNWfAa6ZrxuAdWYCSumIS-HuyKBlRca31AfmU0oYx1mjefCQHnGsFSjcLYi7RJr_yW5_3NOWp29PQ0zNo6YBbuwuDpfkRox33dEp-t6bhyXf-GTt6endLc6DZxjVmOk7R7zCuvaMRHY45RHrLH-Rn8qG324RHb_GQ3F9e3J1fVTc_f1yfn95UTmiVqyUqJZa6aSWIFvulcrACqRVqtbQtNtJKwUvBCida4ZhEbLCTsregEAp0SL7Oc8cYfk-Yshl8crgtP2CYkgEA3irG26agYkZdDClF7M0Y_WDj3gAzr2rNxsxqzataw7QpIkvbyduGaTVg96_pr8sCfJmB3gZj19Enc_-rTGiKdwHAZCG-zwQWE388RpOcx53Dzhdp2XTB__-GF7G1lHg</recordid><startdate>20121115</startdate><enddate>20121115</enddate><creator>Hattori, Fumie</creator><creator>Ohshima, Yasuhiro</creator><creator>Seki, Shizuka</creator><creator>Tsukimoto, Mitsutoshi</creator><creator>Sato, Mitsuru</creator><creator>Takenouchi, Takato</creator><creator>Suzuki, Akina</creator><creator>Takai, Erina</creator><creator>Kitani, Hiroshi</creator><creator>Harada, Hitoshi</creator><creator>Kojima, Shuji</creator><general>Elsevier B.V</general><scope>FBQ</scope><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>20121115</creationdate><title>Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7</title><author>Hattori, Fumie ; Ohshima, Yasuhiro ; Seki, Shizuka ; Tsukimoto, Mitsutoshi ; Sato, Mitsuru ; Takenouchi, Takato ; Suzuki, Akina ; Takai, Erina ; Kitani, Hiroshi ; Harada, Hitoshi ; Kojima, Shuji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-3e88439567146ef38c1b1798e983a6e57a7426efa4c464c07ee5ed77fa18e1983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>acidosis</topic><topic>adenosine</topic><topic>adenosine triphosphate</topic><topic>Adenosine Triphosphate - analogs & derivatives</topic><topic>Adenosine Triphosphate - pharmacology</topic><topic>Adenosine Triphosphate - secretion</topic><topic>Adenosine Triphosphate - therapeutic use</topic><topic>agonists</topic><topic>Animals</topic><topic>antagonists</topic><topic>cell growth</topic><topic>cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Feasibility Studies</topic><topic>Gene Knockdown Techniques</topic><topic>humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>hypoxia</topic><topic>Inhibition</topic><topic>Male</topic><topic>melanoma</topic><topic>Melanoma, Experimental - drug therapy</topic><topic>Melanoma, Experimental - metabolism</topic><topic>Melanoma, Experimental - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Targeted Therapy - methods</topic><topic>Oxidized ATP</topic><topic>P2X7</topic><topic>pharmacology</topic><topic>Purinergic P2X Receptor Antagonists - pharmacology</topic><topic>Purinergic P2X Receptor Antagonists - therapeutic use</topic><topic>Purinergic receptor</topic><topic>Receptors, Purinergic P2X7 - deficiency</topic><topic>Receptors, Purinergic P2X7 - genetics</topic><topic>Receptors, Purinergic P2X7 - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>therapeutics</topic><topic>Tumor growth</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hattori, Fumie</creatorcontrib><creatorcontrib>Ohshima, Yasuhiro</creatorcontrib><creatorcontrib>Seki, Shizuka</creatorcontrib><creatorcontrib>Tsukimoto, Mitsutoshi</creatorcontrib><creatorcontrib>Sato, Mitsuru</creatorcontrib><creatorcontrib>Takenouchi, Takato</creatorcontrib><creatorcontrib>Suzuki, Akina</creatorcontrib><creatorcontrib>Takai, Erina</creatorcontrib><creatorcontrib>Kitani, Hiroshi</creatorcontrib><creatorcontrib>Harada, Hitoshi</creatorcontrib><creatorcontrib>Kojima, Shuji</creatorcontrib><collection>AGRIS</collection><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>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hattori, Fumie</au><au>Ohshima, Yasuhiro</au><au>Seki, Shizuka</au><au>Tsukimoto, Mitsutoshi</au><au>Sato, Mitsuru</au><au>Takenouchi, Takato</au><au>Suzuki, Akina</au><au>Takai, Erina</au><au>Kitani, Hiroshi</au><au>Harada, Hitoshi</au><au>Kojima, Shuji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2012-11-15</date><risdate>2012</risdate><volume>695</volume><issue>1-3</issue><spage>20</spage><epage>26</epage><pages>20-26</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>The P2X7 receptor is not only involved in cell proliferation, but also acts as an adenosine 5′-triphosphate (ATP)-gated non-selective channel, and its expression is increased in human melanoma. An irreversible antagonist of P2X7, such as oxidized ATP (oxATP), might block P2X7 receptor-mediated ATP release and proliferative signaling. Therefore, we carried out basic studies to test this idea and to examine the feasibility of using oxATP to treat B16 melanoma.
We first found that low-pH conditions (mimicking the hypoxia and acidosis commonly seen in solid tumors) induced P2X7 receptor-mediated ATP release from B16 melanoma cells. Then, we compared the proliferation rates of B16 melanoma wild-type cells and B16 P2X7 receptor-knockdown clone (P2X7-KDC) cells in the presence of P2X7 agonists. The proliferation rate, as well as the ATP release, of agonist-treated P2X7-KDC cells was lower than that of agonist-treated wild-type cells. Next, the effect of P2X7 antagonist oxATP on B16 melanoma cell growth was examined in vitro and in vivo. oxATP significantly decreased B16 melanoma cell proliferation in vitro, and also significantly inhibited tumor growth in B16 melanoma-bearing mice.
These data indicate that extracellularly released ATP may serve as an intercellular signaling molecule. We propose that the P2X7 receptor is a promising target for treatment of solid tumors.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>22981895</pmid><doi>10.1016/j.ejphar.2012.09.001</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | acidosis adenosine adenosine triphosphate Adenosine Triphosphate - analogs & derivatives Adenosine Triphosphate - pharmacology Adenosine Triphosphate - secretion Adenosine Triphosphate - therapeutic use agonists Animals antagonists cell growth cell proliferation Cell Proliferation - drug effects Feasibility Studies Gene Knockdown Techniques humans Hydrogen-Ion Concentration hypoxia Inhibition Male melanoma Melanoma, Experimental - drug therapy Melanoma, Experimental - metabolism Melanoma, Experimental - pathology Mice Mice, Inbred C57BL Molecular Targeted Therapy - methods Oxidized ATP P2X7 pharmacology Purinergic P2X Receptor Antagonists - pharmacology Purinergic P2X Receptor Antagonists - therapeutic use Purinergic receptor Receptors, Purinergic P2X7 - deficiency Receptors, Purinergic P2X7 - genetics Receptors, Purinergic P2X7 - metabolism Signal Transduction - drug effects therapeutics Tumor growth |
| title | Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7 |
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