Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways
Disulfiram/copper (DSF/Cu) is a promising antitumor reagent for clinical application due to its excellent anticancer activity and safety. However, the anticancer mechanism of DSF/Cu has not been fully elucidated. Our study showed that DSF/Cu strongly induced cytotoxic effects on both nasopharyngeal...
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| Veröffentlicht in: | Cancers 2020-01, Vol.12 (1), p.138 |
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| creator | Li, Yiqiu Chen, Fangfang Chen, Jun Chan, Siocheong He, Yi Liu, Wanli Zhang, Ge |
| description | Disulfiram/copper (DSF/Cu) is a promising antitumor reagent for clinical application due to its excellent anticancer activity and safety. However, the anticancer mechanism of DSF/Cu has not been fully elucidated. Our study showed that DSF/Cu strongly induced cytotoxic effects on both nasopharyngeal carcinoma (NPC) cells and α-smooth muscle actin (α-SMA)-positive fibroblasts. Fluorescence activated cell sorting (FACS) analysis further showed that DSF/Cu induced a higher late apoptosis rate in α-SMA-positive fibroblasts than in tumor cells, and DSF/Cu promoted apoptosis and necrosis by an aldehyde dehydrogenase (ALDH)-independent method. Furthermore, we found that the antitumor activity of DSF/Cu against NPC cells occurred through ROS/MAPK and p53-mediated ferroptosis pathways, and that the ROS scavenger
-acetyl-l-cysteine (NAC) could reverse the cellular and lipid ROS levels. In 5-8F xenografts, both TUNEL and immunohistochemical (IHC) analyses indicated that DSF/Cu could induce apoptosis and inactivate cancer-associated fibroblasts (CAFs) by inhibiting the expression of α-SMA. In addition, combined with cisplatin (CDDP), DSF/Cu was well tolerated in vivo and could significantly suppress the growth of NPC tissues. Our study demonstrated that DSF/Cu induced antitumor activity against both tumor cells, as well as CAFs and suggested that the use of DSF/Cu as an adjunctive therapy for NPC is worthy of consideration. |
| doi_str_mv | 10.3390/cancers12010138 |
| format | Article |
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-acetyl-l-cysteine (NAC) could reverse the cellular and lipid ROS levels. In 5-8F xenografts, both TUNEL and immunohistochemical (IHC) analyses indicated that DSF/Cu could induce apoptosis and inactivate cancer-associated fibroblasts (CAFs) by inhibiting the expression of α-SMA. In addition, combined with cisplatin (CDDP), DSF/Cu was well tolerated in vivo and could significantly suppress the growth of NPC tissues. Our study demonstrated that DSF/Cu induced antitumor activity against both tumor cells, as well as CAFs and suggested that the use of DSF/Cu as an adjunctive therapy for NPC is worthy of consideration.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12010138</identifier><identifier>PMID: 31935835</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Acetylcysteine ; Actin ; Aldehyde dehydrogenase ; Antitumor activity ; Apoptosis ; Cancer therapies ; Cell cycle ; Cisplatin ; Copper ; Cytotoxicity ; Disulfiram ; Drug dosages ; Drug withdrawal ; Ferroptosis ; Fibroblasts ; Flow cytometry ; Gene expression ; Lipid peroxidation ; Lipids ; MAP kinase ; Nasopharyngeal carcinoma ; Radiation ; Smooth muscle ; Tumor cells ; Xenografts</subject><ispartof>Cancers, 2020-01, Vol.12 (1), p.138</ispartof><rights>2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-212b7edb2e858559afa334b4454c566a3eaa938104a97f7de8d10a5872c3bf1d3</citedby><cites>FETCH-LOGICAL-c533t-212b7edb2e858559afa334b4454c566a3eaa938104a97f7de8d10a5872c3bf1d3</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/PMC7017005/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017005/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31935835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yiqiu</creatorcontrib><creatorcontrib>Chen, Fangfang</creatorcontrib><creatorcontrib>Chen, Jun</creatorcontrib><creatorcontrib>Chan, Siocheong</creatorcontrib><creatorcontrib>He, Yi</creatorcontrib><creatorcontrib>Liu, Wanli</creatorcontrib><creatorcontrib>Zhang, Ge</creatorcontrib><title>Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Disulfiram/copper (DSF/Cu) is a promising antitumor reagent for clinical application due to its excellent anticancer activity and safety. However, the anticancer mechanism of DSF/Cu has not been fully elucidated. Our study showed that DSF/Cu strongly induced cytotoxic effects on both nasopharyngeal carcinoma (NPC) cells and α-smooth muscle actin (α-SMA)-positive fibroblasts. Fluorescence activated cell sorting (FACS) analysis further showed that DSF/Cu induced a higher late apoptosis rate in α-SMA-positive fibroblasts than in tumor cells, and DSF/Cu promoted apoptosis and necrosis by an aldehyde dehydrogenase (ALDH)-independent method. Furthermore, we found that the antitumor activity of DSF/Cu against NPC cells occurred through ROS/MAPK and p53-mediated ferroptosis pathways, and that the ROS scavenger
-acetyl-l-cysteine (NAC) could reverse the cellular and lipid ROS levels. In 5-8F xenografts, both TUNEL and immunohistochemical (IHC) analyses indicated that DSF/Cu could induce apoptosis and inactivate cancer-associated fibroblasts (CAFs) by inhibiting the expression of α-SMA. In addition, combined with cisplatin (CDDP), DSF/Cu was well tolerated in vivo and could significantly suppress the growth of NPC tissues. Our study demonstrated that DSF/Cu induced antitumor activity against both tumor cells, as well as CAFs and suggested that the use of DSF/Cu as an adjunctive therapy for NPC is worthy of consideration.</description><subject>Acetylcysteine</subject><subject>Actin</subject><subject>Aldehyde dehydrogenase</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cisplatin</subject><subject>Copper</subject><subject>Cytotoxicity</subject><subject>Disulfiram</subject><subject>Drug dosages</subject><subject>Drug withdrawal</subject><subject>Ferroptosis</subject><subject>Fibroblasts</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Lipid peroxidation</subject><subject>Lipids</subject><subject>MAP kinase</subject><subject>Nasopharyngeal carcinoma</subject><subject>Radiation</subject><subject>Smooth muscle</subject><subject>Tumor cells</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkk1v1DAQhiMEolXpmRuyxIVLWDsT5-OCtAS2VBRa8XGOJo6zcZXYqccp2p_Tf0raLlWpL7Zmnnk173ii6LXg7wFKvlJolfYkEi64gOJZdJjwPImzrEyfP3ofRMdEl3w5ACLP8pfRAYgSZAHyMLr5ZGgeOuNxXFVumrRnp7adlSa2tsGEeXSerVUw1ybsGG7RWArsows9-47kph79zm41Dqy664ZVehiIoW33gXhN5JTBoFu2MY13zYAUiIXeu3nbsx_nP1ff1hdf70o22ns3BUeG2AWG_g_u6FX0osOB9PH-Pop-bz7_qr7EZ-cnp9X6LFYSIMSJSJpct02iC1lIWWKHAGmTpjJVMssQNGIJheAplnmXt7poBUdZ5ImCphMtHEUf7nWnuRl1q7QNHod68mZcPNYOTf1_xpq-3rrrOuci51wuAu_2At5dzZpCPRpSyzjQajdTnQAUZVFAeYu-fYJeutnbxV6dyDTPRFpCtlCre0p5R-R199CM4PXtBtRPNmCpePPYwwP_77_hL8u3sOs</recordid><startdate>20200106</startdate><enddate>20200106</enddate><creator>Li, Yiqiu</creator><creator>Chen, Fangfang</creator><creator>Chen, Jun</creator><creator>Chan, Siocheong</creator><creator>He, Yi</creator><creator>Liu, Wanli</creator><creator>Zhang, Ge</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</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>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200106</creationdate><title>Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways</title><author>Li, Yiqiu ; Chen, Fangfang ; Chen, Jun ; Chan, Siocheong ; He, Yi ; Liu, Wanli ; Zhang, Ge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c533t-212b7edb2e858559afa334b4454c566a3eaa938104a97f7de8d10a5872c3bf1d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetylcysteine</topic><topic>Actin</topic><topic>Aldehyde dehydrogenase</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cisplatin</topic><topic>Copper</topic><topic>Cytotoxicity</topic><topic>Disulfiram</topic><topic>Drug dosages</topic><topic>Drug withdrawal</topic><topic>Ferroptosis</topic><topic>Fibroblasts</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Lipid peroxidation</topic><topic>Lipids</topic><topic>MAP kinase</topic><topic>Nasopharyngeal carcinoma</topic><topic>Radiation</topic><topic>Smooth muscle</topic><topic>Tumor cells</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yiqiu</creatorcontrib><creatorcontrib>Chen, Fangfang</creatorcontrib><creatorcontrib>Chen, Jun</creatorcontrib><creatorcontrib>Chan, Siocheong</creatorcontrib><creatorcontrib>He, Yi</creatorcontrib><creatorcontrib>Liu, Wanli</creatorcontrib><creatorcontrib>Zhang, Ge</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</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>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yiqiu</au><au>Chen, Fangfang</au><au>Chen, Jun</au><au>Chan, Siocheong</au><au>He, Yi</au><au>Liu, Wanli</au><au>Zhang, Ge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2020-01-06</date><risdate>2020</risdate><volume>12</volume><issue>1</issue><spage>138</spage><pages>138-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Disulfiram/copper (DSF/Cu) is a promising antitumor reagent for clinical application due to its excellent anticancer activity and safety. However, the anticancer mechanism of DSF/Cu has not been fully elucidated. Our study showed that DSF/Cu strongly induced cytotoxic effects on both nasopharyngeal carcinoma (NPC) cells and α-smooth muscle actin (α-SMA)-positive fibroblasts. Fluorescence activated cell sorting (FACS) analysis further showed that DSF/Cu induced a higher late apoptosis rate in α-SMA-positive fibroblasts than in tumor cells, and DSF/Cu promoted apoptosis and necrosis by an aldehyde dehydrogenase (ALDH)-independent method. Furthermore, we found that the antitumor activity of DSF/Cu against NPC cells occurred through ROS/MAPK and p53-mediated ferroptosis pathways, and that the ROS scavenger
-acetyl-l-cysteine (NAC) could reverse the cellular and lipid ROS levels. In 5-8F xenografts, both TUNEL and immunohistochemical (IHC) analyses indicated that DSF/Cu could induce apoptosis and inactivate cancer-associated fibroblasts (CAFs) by inhibiting the expression of α-SMA. In addition, combined with cisplatin (CDDP), DSF/Cu was well tolerated in vivo and could significantly suppress the growth of NPC tissues. Our study demonstrated that DSF/Cu induced antitumor activity against both tumor cells, as well as CAFs and suggested that the use of DSF/Cu as an adjunctive therapy for NPC is worthy of consideration.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31935835</pmid><doi>10.3390/cancers12010138</doi><oa>free_for_read</oa></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Acetylcysteine Actin Aldehyde dehydrogenase Antitumor activity Apoptosis Cancer therapies Cell cycle Cisplatin Copper Cytotoxicity Disulfiram Drug dosages Drug withdrawal Ferroptosis Fibroblasts Flow cytometry Gene expression Lipid peroxidation Lipids MAP kinase Nasopharyngeal carcinoma Radiation Smooth muscle Tumor cells Xenografts |
| title | Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways |
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