Iron chelators induce autophagic cell death in multiple myeloma cells
Abstract We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cyt...
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| Veröffentlicht in: | Leukemia research 2014-08, Vol.38 (8), p.988-996 |
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| container_title | Leukemia research |
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| creator | Pullarkat, Vinod Meng, Zhuo Donohue, Cecile Yamamoto, Vicky N Tomassetti, Sarah Bhatia, Ravi Krishnan, Amrita Forman, Stephen J Synold, Timothy W |
| description | Abstract We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma. |
| doi_str_mv | 10.1016/j.leukres.2014.06.005 |
| format | Article |
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These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.</description><identifier>ISSN: 0145-2126</identifier><identifier>EISSN: 1873-5835</identifier><identifier>DOI: 10.1016/j.leukres.2014.06.005</identifier><identifier>PMID: 24998390</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Autophagy ; Autophagy - drug effects ; Benzoates - pharmacology ; Benzoates - therapeutic use ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Deferasirox ; Deferoxamine ; Deferoxamine - pharmacology ; Deferoxamine - therapeutic use ; Drug Evaluation, Preclinical ; Hematology, Oncology and Palliative Medicine ; Humans ; Iron Chelating Agents - pharmacology ; Iron Chelating Agents - therapeutic use ; Iron chelation ; mTOR ; Multiple myeloma ; Multiple Myeloma - drug therapy ; Multiple Myeloma - pathology ; p70S6 kinase ; Primary Cell Culture ; Reactive Oxygen Species - metabolism ; Triazoles - pharmacology ; Triazoles - therapeutic use</subject><ispartof>Leukemia research, 2014-08, Vol.38 (8), p.988-996</ispartof><rights>Elsevier Ltd</rights><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c519t-130bc96fe7d1b152f1f61390643ef2b0fbc0b182fa53812c1063c2f21e57b89f3</citedby><cites>FETCH-LOGICAL-c519t-130bc96fe7d1b152f1f61390643ef2b0fbc0b182fa53812c1063c2f21e57b89f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.leukres.2014.06.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24998390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pullarkat, Vinod</creatorcontrib><creatorcontrib>Meng, Zhuo</creatorcontrib><creatorcontrib>Donohue, Cecile</creatorcontrib><creatorcontrib>Yamamoto, Vicky N</creatorcontrib><creatorcontrib>Tomassetti, Sarah</creatorcontrib><creatorcontrib>Bhatia, Ravi</creatorcontrib><creatorcontrib>Krishnan, Amrita</creatorcontrib><creatorcontrib>Forman, Stephen J</creatorcontrib><creatorcontrib>Synold, Timothy W</creatorcontrib><title>Iron chelators induce autophagic cell death in multiple myeloma cells</title><title>Leukemia research</title><addtitle>Leuk Res</addtitle><description>Abstract We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.</description><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Benzoates - pharmacology</subject><subject>Benzoates - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Deferasirox</subject><subject>Deferoxamine</subject><subject>Deferoxamine - pharmacology</subject><subject>Deferoxamine - therapeutic use</subject><subject>Drug Evaluation, Preclinical</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Iron Chelating Agents - therapeutic use</subject><subject>Iron chelation</subject><subject>mTOR</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - pathology</subject><subject>p70S6 kinase</subject><subject>Primary Cell Culture</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Triazoles - pharmacology</subject><subject>Triazoles - therapeutic use</subject><issn>0145-2126</issn><issn>1873-5835</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi0EotvCTwDlyCXBY8dOfAGhqtBKlTi0nC3HGbPeOsliJ5X23-OwCwcu7WkO7zMfeoaQd0AroCA_7qqAy0PEVDEKdUVlRal4QTbQNrwULRcvySYHomTA5Bk5T2lHM6FAvSZnrFaq5YpuyNVNnMbCbjGYeYqp8GO_WCzMMk_7rfnpbWExhKJHM29zWAxLmP0-YDEcMEyD-ROnN-SVMyHh21O9ID--Xt1fXpe337_dXH65La0ANZfAaWeVdNj00IFgDpyEfIasOTrWUddZ2kHLnBG8BWaBSm6ZY4Ci6Vrl-AX5cJy7j9OvBdOsB5_WC8yI05I0CEkB8prmGWjdtJwzoTIqjqiNU0oRnd5HP5h40ED1Klvv9Em2XmVrKnVWmfven1Ys3YD9v66_djPw-QhgdvLoMepkPY4Wex_Rzrqf_JMrPv03wQY_emvCAx4w7aYljlm4Bp2Ypvpu_fj6cKgphbZm_Dfo56bI</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Pullarkat, Vinod</creator><creator>Meng, Zhuo</creator><creator>Donohue, Cecile</creator><creator>Yamamoto, Vicky N</creator><creator>Tomassetti, Sarah</creator><creator>Bhatia, Ravi</creator><creator>Krishnan, Amrita</creator><creator>Forman, Stephen J</creator><creator>Synold, Timothy W</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><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20140801</creationdate><title>Iron chelators induce autophagic cell death in multiple myeloma cells</title><author>Pullarkat, Vinod ; Meng, Zhuo ; Donohue, Cecile ; Yamamoto, Vicky N ; Tomassetti, Sarah ; Bhatia, Ravi ; Krishnan, Amrita ; Forman, Stephen J ; Synold, Timothy W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c519t-130bc96fe7d1b152f1f61390643ef2b0fbc0b182fa53812c1063c2f21e57b89f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Benzoates - pharmacology</topic><topic>Benzoates - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Deferasirox</topic><topic>Deferoxamine</topic><topic>Deferoxamine - pharmacology</topic><topic>Deferoxamine - therapeutic use</topic><topic>Drug Evaluation, Preclinical</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Iron Chelating Agents - pharmacology</topic><topic>Iron Chelating Agents - therapeutic use</topic><topic>Iron chelation</topic><topic>mTOR</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - pathology</topic><topic>p70S6 kinase</topic><topic>Primary Cell Culture</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Triazoles - pharmacology</topic><topic>Triazoles - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pullarkat, Vinod</creatorcontrib><creatorcontrib>Meng, Zhuo</creatorcontrib><creatorcontrib>Donohue, Cecile</creatorcontrib><creatorcontrib>Yamamoto, Vicky N</creatorcontrib><creatorcontrib>Tomassetti, Sarah</creatorcontrib><creatorcontrib>Bhatia, Ravi</creatorcontrib><creatorcontrib>Krishnan, Amrita</creatorcontrib><creatorcontrib>Forman, Stephen J</creatorcontrib><creatorcontrib>Synold, Timothy W</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><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Leukemia research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pullarkat, Vinod</au><au>Meng, Zhuo</au><au>Donohue, Cecile</au><au>Yamamoto, Vicky N</au><au>Tomassetti, Sarah</au><au>Bhatia, Ravi</au><au>Krishnan, Amrita</au><au>Forman, Stephen J</au><au>Synold, Timothy W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Iron chelators induce autophagic cell death in multiple myeloma cells</atitle><jtitle>Leukemia research</jtitle><addtitle>Leuk Res</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>38</volume><issue>8</issue><spage>988</spage><epage>996</epage><pages>988-996</pages><issn>0145-2126</issn><eissn>1873-5835</eissn><abstract>Abstract We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24998390</pmid><doi>10.1016/j.leukres.2014.06.005</doi><tpages>9</tpages></addata></record> |
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| subjects | Autophagy Autophagy - drug effects Benzoates - pharmacology Benzoates - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Deferasirox Deferoxamine Deferoxamine - pharmacology Deferoxamine - therapeutic use Drug Evaluation, Preclinical Hematology, Oncology and Palliative Medicine Humans Iron Chelating Agents - pharmacology Iron Chelating Agents - therapeutic use Iron chelation mTOR Multiple myeloma Multiple Myeloma - drug therapy Multiple Myeloma - pathology p70S6 kinase Primary Cell Culture Reactive Oxygen Species - metabolism Triazoles - pharmacology Triazoles - therapeutic use |
| title | Iron chelators induce autophagic cell death in multiple myeloma cells |
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