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A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo
In this study, a Cu 2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly...
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| Published in: | Free radical biology & medicine 2011-01, Vol.50 (1), p.110-121 |
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| container_end_page | 121 |
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| container_title | Free radical biology & medicine |
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| creator | Hancock, Chad N. Stockwin, Luke H. Han, Bingnan Divelbiss, Raymond D. Jun, Jung Ho Malhotra, Sanjay V. Hollingshead, Melinda G. Newton, Dianne L. |
| description | In this study, a Cu
2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu
2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu
2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant
N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu
2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu
2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu
2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu
2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu
2+ is a potent oxidative stress inducer worthy of further preclinical investigation. |
| doi_str_mv | 10.1016/j.freeradbiomed.2010.10.696 |
| format | article |
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2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu
2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu
2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant
N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu
2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu
2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu
2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu
2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu
2+ is a potent oxidative stress inducer worthy of further preclinical investigation.</description><identifier>ISSN: 0891-5849</identifier><identifier>ISSN: 1873-4596</identifier><identifier>EISSN: 1873-4596</identifier><identifier>DOI: 10.1016/j.freeradbiomed.2010.10.696</identifier><identifier>PMID: 20971185</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>acetylcysteine ; Animals ; anticarcinogenic activity ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; antioxidants ; autophagy ; biosynthesis ; Cell Proliferation - drug effects ; Chelating Agents - metabolism ; Chelating Agents - pharmacology ; chelation ; Copper ; Copper - metabolism ; Down-Regulation - drug effects ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; ER stress ; Female ; Free radicals ; glutathione ; HL-60 Cells ; Humans ; iron ; Macroautophagy ; Mice ; Mice, Nude ; microarray technology ; Neoplasms - metabolism ; Neoplasms - pathology ; Organometallic Compounds - pharmacology ; Organometallic Compounds - therapeutic use ; Oxidants - pharmacology ; Oxidants - therapeutic use ; Oxidative stress ; Oxidative Stress - drug effects ; thiols ; Thiosemicarbazone ; Thiosemicarbazones - pharmacology ; Thiosemicarbazones - therapeutic use ; Tumor Cells, Cultured ; Unfolded Protein Response - drug effects ; Up-Regulation - drug effects ; UPR ; Xenograft Model Antitumor Assays</subject><ispartof>Free radical biology & medicine, 2011-01, Vol.50 (1), p.110-121</ispartof><rights>2010 Elsevier Inc.</rights><rights>Copyright © 2010 Elsevier Inc. All rights reserved.</rights><rights>2010 Elsevier Inc. All rights reserved. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-e7aa9ce14dc1c9aa90c4fb0c6678dd1ca97167d87eddbf193afbd0fcb6a2f2b33</citedby><cites>FETCH-LOGICAL-c546t-e7aa9ce14dc1c9aa90c4fb0c6678dd1ca97167d87eddbf193afbd0fcb6a2f2b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20971185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hancock, Chad N.</creatorcontrib><creatorcontrib>Stockwin, Luke H.</creatorcontrib><creatorcontrib>Han, Bingnan</creatorcontrib><creatorcontrib>Divelbiss, Raymond D.</creatorcontrib><creatorcontrib>Jun, Jung Ho</creatorcontrib><creatorcontrib>Malhotra, Sanjay V.</creatorcontrib><creatorcontrib>Hollingshead, Melinda G.</creatorcontrib><creatorcontrib>Newton, Dianne L.</creatorcontrib><title>A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo</title><title>Free radical biology & medicine</title><addtitle>Free Radic Biol Med</addtitle><description>In this study, a Cu
2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu
2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu
2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant
N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu
2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu
2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu
2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu
2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu
2+ is a potent oxidative stress inducer worthy of further preclinical investigation.</description><subject>acetylcysteine</subject><subject>Animals</subject><subject>anticarcinogenic activity</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>antioxidants</subject><subject>autophagy</subject><subject>biosynthesis</subject><subject>Cell Proliferation - drug effects</subject><subject>Chelating Agents - metabolism</subject><subject>Chelating Agents - pharmacology</subject><subject>chelation</subject><subject>Copper</subject><subject>Copper - metabolism</subject><subject>Down-Regulation - drug effects</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>ER stress</subject><subject>Female</subject><subject>Free radicals</subject><subject>glutathione</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>iron</subject><subject>Macroautophagy</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>microarray technology</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Organometallic Compounds - therapeutic use</subject><subject>Oxidants - pharmacology</subject><subject>Oxidants - therapeutic use</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>thiols</subject><subject>Thiosemicarbazone</subject><subject>Thiosemicarbazones - pharmacology</subject><subject>Thiosemicarbazones - therapeutic use</subject><subject>Tumor Cells, Cultured</subject><subject>Unfolded Protein Response - drug effects</subject><subject>Up-Regulation - drug effects</subject><subject>UPR</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0891-5849</issn><issn>1873-4596</issn><issn>1873-4596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqNUduO0zAUjBCILQu_AJZ42Kd07ThxbCEhrapykVYgseyz5djHjas0LrYTbj-PS8uKfYInX2bOaM5MUbwkeEkwYZfbpQ0AQZnO-R2YZYV_I0sm2INiQXhLy7oR7GGxwFyQsuG1OCuexLjFGNcN5Y-LswqLlhDeLIqfV0j7_R4C0j0MKgHyFqXe-Qg7p1Xo1A8_Avpws0KMi4bWyI1m0hCR_-aMSm6Gy_UnFFOAGJEaTcZ717kUUZp2PqBN8F9Tn3_R7FLwJ0p-zP5p8ciqIcKz03le3L5Zf169K68_vn2_uroudVOzVEKrlNBAaqOJFvmOdW07rBlruTFEq7wLaw1vwZjOEkGV7Qy2umOqslVH6Xnx-qi7n7ocmIYxBTXIfXA7Fb5Lr5y8j4yulxs_S4pJTTnPAhcngeC_TBCT3LmoYRjUCH6KUjBOGpZD_SeTVxVltOYkM18dmTr4GAPYOz8Ey0PPcivv9SwPPR_A3HOefv73Snezf4rNhBdHglVeqk1wUd7eZIUGY5Id0IOB9ZEBOfrZQZBROxg1GBdAJ2m8-y8rvwBsac3L</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Hancock, Chad N.</creator><creator>Stockwin, Luke H.</creator><creator>Han, Bingnan</creator><creator>Divelbiss, Raymond D.</creator><creator>Jun, Jung Ho</creator><creator>Malhotra, Sanjay V.</creator><creator>Hollingshead, Melinda G.</creator><creator>Newton, Dianne L.</creator><general>Elsevier Inc</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><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>20110101</creationdate><title>A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo</title><author>Hancock, Chad N. ; Stockwin, Luke H. ; Han, Bingnan ; Divelbiss, Raymond D. ; Jun, Jung Ho ; Malhotra, Sanjay V. ; Hollingshead, Melinda G. ; Newton, Dianne L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c546t-e7aa9ce14dc1c9aa90c4fb0c6678dd1ca97167d87eddbf193afbd0fcb6a2f2b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>acetylcysteine</topic><topic>Animals</topic><topic>anticarcinogenic activity</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>antioxidants</topic><topic>autophagy</topic><topic>biosynthesis</topic><topic>Cell Proliferation - drug effects</topic><topic>Chelating Agents - metabolism</topic><topic>Chelating Agents - pharmacology</topic><topic>chelation</topic><topic>Copper</topic><topic>Copper - metabolism</topic><topic>Down-Regulation - drug effects</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>ER stress</topic><topic>Female</topic><topic>Free radicals</topic><topic>glutathione</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>iron</topic><topic>Macroautophagy</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>microarray technology</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Organometallic Compounds - therapeutic use</topic><topic>Oxidants - pharmacology</topic><topic>Oxidants - therapeutic use</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>thiols</topic><topic>Thiosemicarbazone</topic><topic>Thiosemicarbazones - pharmacology</topic><topic>Thiosemicarbazones - therapeutic use</topic><topic>Tumor Cells, Cultured</topic><topic>Unfolded Protein Response - drug effects</topic><topic>Up-Regulation - drug effects</topic><topic>UPR</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hancock, Chad N.</creatorcontrib><creatorcontrib>Stockwin, Luke H.</creatorcontrib><creatorcontrib>Han, Bingnan</creatorcontrib><creatorcontrib>Divelbiss, Raymond D.</creatorcontrib><creatorcontrib>Jun, Jung Ho</creatorcontrib><creatorcontrib>Malhotra, Sanjay V.</creatorcontrib><creatorcontrib>Hollingshead, Melinda G.</creatorcontrib><creatorcontrib>Newton, Dianne L.</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><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Free radical biology & medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hancock, Chad N.</au><au>Stockwin, Luke H.</au><au>Han, Bingnan</au><au>Divelbiss, Raymond D.</au><au>Jun, Jung Ho</au><au>Malhotra, Sanjay V.</au><au>Hollingshead, Melinda G.</au><au>Newton, Dianne L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo</atitle><jtitle>Free radical biology & medicine</jtitle><addtitle>Free Radic Biol Med</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>50</volume><issue>1</issue><spage>110</spage><epage>121</epage><pages>110-121</pages><issn>0891-5849</issn><issn>1873-4596</issn><eissn>1873-4596</eissn><abstract>In this study, a Cu
2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu
2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu
2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant
N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu
2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu
2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu
2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu
2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu
2+ is a potent oxidative stress inducer worthy of further preclinical investigation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20971185</pmid><doi>10.1016/j.freeradbiomed.2010.10.696</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0891-5849 |
| ispartof | Free radical biology & medicine, 2011-01, Vol.50 (1), p.110-121 |
| issn | 0891-5849 1873-4596 1873-4596 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3014388 |
| source | ScienceDirect Journals |
| subjects | acetylcysteine Animals anticarcinogenic activity Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use antioxidants autophagy biosynthesis Cell Proliferation - drug effects Chelating Agents - metabolism Chelating Agents - pharmacology chelation Copper Copper - metabolism Down-Regulation - drug effects Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism ER stress Female Free radicals glutathione HL-60 Cells Humans iron Macroautophagy Mice Mice, Nude microarray technology Neoplasms - metabolism Neoplasms - pathology Organometallic Compounds - pharmacology Organometallic Compounds - therapeutic use Oxidants - pharmacology Oxidants - therapeutic use Oxidative stress Oxidative Stress - drug effects thiols Thiosemicarbazone Thiosemicarbazones - pharmacology Thiosemicarbazones - therapeutic use Tumor Cells, Cultured Unfolded Protein Response - drug effects Up-Regulation - drug effects UPR Xenograft Model Antitumor Assays |
| title | A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo |
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