Current Biomedical Use of Copper Chelation Therapy
Identifieur interne : 000163 ( Pmc/Checkpoint ); précédent : 000162; suivant : 000164Current Biomedical Use of Copper Chelation Therapy
Auteurs : Silvia Baldari [Italie] ; Giuliana Di Rocco ; Gabriele ToiettaSource :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2020.
Abstract
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.
Url:
DOI: 10.3390/ijms21031069
PubMed: 32041110
PubMed Central: 7037088
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Current Biomedical Use of Copper Chelation Therapy</title><author><name sortKey="Baldari, Silvia" sort="Baldari, Silvia" uniqKey="Baldari S" first="Silvia" last="Baldari">Silvia Baldari</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-ijms-21-01069">Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina</wicri:regionArea><wicri:noRegion>04100 Latina</wicri:noRegion></affiliation></author><author><name sortKey="Di Rocco, Giuliana" sort="Di Rocco, Giuliana" uniqKey="Di Rocco G" first="Giuliana" last="Di Rocco">Giuliana Di Rocco</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation></author><author><name sortKey="Toietta, Gabriele" sort="Toietta, Gabriele" uniqKey="Toietta G" first="Gabriele" last="Toietta">Gabriele Toietta</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32041110</idno><idno type="pmc">7037088</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037088</idno><idno type="RBID">PMC:7037088</idno><idno type="doi">10.3390/ijms21031069</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000A31</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A31</idno><idno type="wicri:Area/Pmc/Curation">000A31</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A31</idno><idno type="wicri:Area/Pmc/Checkpoint">000163</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000163</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Current Biomedical Use of Copper Chelation Therapy</title><author><name sortKey="Baldari, Silvia" sort="Baldari, Silvia" uniqKey="Baldari S" first="Silvia" last="Baldari">Silvia Baldari</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-ijms-21-01069">Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina</wicri:regionArea><wicri:noRegion>04100 Latina</wicri:noRegion></affiliation></author><author><name sortKey="Di Rocco, Giuliana" sort="Di Rocco, Giuliana" uniqKey="Di Rocco G" first="Giuliana" last="Di Rocco">Giuliana Di Rocco</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation></author><author><name sortKey="Toietta, Gabriele" sort="Toietta, Gabriele" uniqKey="Toietta G" first="Gabriele" last="Toietta">Gabriele Toietta</name><affiliation><nlm:aff id="af1-ijms-21-01069">Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Blockhuys, S" uniqKey="Blockhuys S">S. Blockhuys</name></author><author><name sortKey="Celauro, E" uniqKey="Celauro E">E. Celauro</name></author><author><name sortKey="Hildesjo, C" uniqKey="Hildesjo C">C. Hildesjö</name></author><author><name sortKey="Feizi, A" uniqKey="Feizi A">A. Feizi</name></author><author><name sortKey="St L, O" uniqKey="St L O">O. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id><journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id><journal-id journal-id-type="publisher-id">ijms</journal-id><journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title></journal-title-group><issn pub-type="epub">1422-0067</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32041110</article-id><article-id pub-id-type="pmc">7037088</article-id><article-id pub-id-type="doi">10.3390/ijms21031069</article-id><article-id pub-id-type="publisher-id">ijms-21-01069</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Current Biomedical Use of Copper Chelation Therapy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Baldari</surname><given-names>Silvia</given-names></name><xref ref-type="aff" rid="af1-ijms-21-01069">1</xref><xref ref-type="aff" rid="af2-ijms-21-01069">2</xref></contrib><contrib contrib-type="author"><name><surname>Di Rocco</surname><given-names>Giuliana</given-names></name><xref ref-type="aff" rid="af1-ijms-21-01069">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4182-2468</contrib-id><name><surname>Toietta</surname><given-names>Gabriele</given-names></name><xref ref-type="aff" rid="af1-ijms-21-01069">1</xref><xref rid="c1-ijms-21-01069" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-ijms-21-01069"><label>1</label>Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy;<email>silvia.baldari@ifo.gov.it</email> (S.B.);<email>giuliana.dirocco@ifo.gov.it</email> (G.D.R.)</aff><aff id="af2-ijms-21-01069"><label>2</label>Department of Medical Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, C.so della Repubblica 79, 04100 Latina, Italy</aff><author-notes><corresp id="c1-ijms-21-01069"><label>*</label>Correspondence: <email>gabriele.toietta@ifo.gov.it</email>; Tel.: +39-06-5266-2604</corresp></author-notes><pub-date pub-type="epub"><day>06</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>2</month><year>2020</year></pub-date><volume>21</volume><issue>3</issue><elocation-id>1069</elocation-id><history><date date-type="received"><day>09</day><month>1</month><year>2020</year></date><date date-type="accepted"><day>04</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.</p></abstract><kwd-group><kwd>copper</kwd><kwd>chelation therapy</kwd><kwd>therapeutic chelation</kwd><kwd>metal homeostasis</kwd><kwd>cancer</kwd><kwd>metalloproteins</kwd></kwd-group></article-meta></front><floats-group><fig id="ijms-21-01069-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Schematic representation of the main genes involved in the antitumoral effects of copper chelation therapy [<xref rid="B1-ijms-21-01069" ref-type="bibr">1</xref>].</p></caption><graphic xlink:href="ijms-21-01069-g001"></graphic></fig><table-wrap id="ijms-21-01069-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-21-01069-t001_Table 1</object-id><label>Table 1</label><caption><p>Main copper chelating drugs.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound Name</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Abbreviation</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Chemical Formula</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Structural Formula</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">D-penicillamine: (S)-2-amino-3-mercapto-3-methylbutanoic acid</td><td align="center" valign="middle" rowspan="1" colspan="1">DPA</td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>5</sub>H<sub>11</sub>NO<sub>2</sub>S</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-01069-i001.jpg"></inline-graphic></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Tetrathiomolybdate</td><td align="center" valign="middle" rowspan="1" colspan="1">TM</td><td align="center" valign="middle" rowspan="1" colspan="1">MoS<sub>4</sub></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-01069-i002.jpg"></inline-graphic></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Trientine: triethylenetetramine dihydrochloride</td><td align="center" valign="middle" rowspan="1" colspan="1">TETA</td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>6</sub>H<sub>18</sub>N<sub>4</sub></td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-01069-i003.jpg"></inline-graphic></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">5,7-Dichloro-2[(dimethylamino)methyl]quinolin-8-ol</td><td align="center" valign="middle" rowspan="1" colspan="1">PBT2</td><td align="center" valign="middle" rowspan="1" colspan="1">C<sub>12</sub>H<sub>12</sub>Cl<sub>2</sub>N<sub>2</sub>O</td><td align="center" valign="middle" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-01069-i004.jpg"></inline-graphic></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2,3-Dimercaptosuccinic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DMSA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">C<sub>4</sub>H<sub>6</sub>O<sub>4</sub>S<sub>2</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="ijms-21-01069-i005.jpg"></inline-graphic></td></tr></tbody></table><table-wrap-foot><fn><p>Structural formulas collected from the DrugBank public database (<uri xlink:href="http://www.drugbank.ca/">http://www.drugbank.ca/</uri>).</p></fn></table-wrap-foot></table-wrap><table-wrap id="ijms-21-01069-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-21-01069-t002_Table 2</object-id><label>Table 2</label><caption><p>Copper chelation therapy clinical trials for non-tumoral disorders.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Condition</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">NCT Number/Reference</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Trial Phase</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Patients Enrolled</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drug/Intervention</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Status</th></tr></thead><tbody><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Wilson’s Disease</td><td align="center" valign="middle" rowspan="1" colspan="1">NCT02273596</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">28</td><td align="center" valign="middle" rowspan="1" colspan="1">WTX101</td><td align="center" valign="middle" rowspan="1" colspan="1">completed</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NCT03299829</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" rowspan="1" colspan="1">50</td><td align="center" valign="middle" rowspan="1" colspan="1">TETA</td><td align="center" valign="middle" rowspan="1" colspan="1">recruiting</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">NCT01472874</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">TETA</td><td align="center" valign="middle" rowspan="1" colspan="1">completed</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01378182</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MSC transplant</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">completed</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Alzheimer’s disease</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B60-ijms-21-01069" ref-type="bibr">60</xref>]</td><td align="center" valign="middle" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" rowspan="1" colspan="1">34</td><td align="center" valign="middle" rowspan="1" colspan="1">DPA</td><td align="center" valign="middle" rowspan="1" colspan="1">terminated</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT00471211 [<xref rid="B61-ijms-21-01069" ref-type="bibr">61</xref>]</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">78</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBT2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">completed</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Idiopathic pulmonary fibrosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT00189176</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">I/II</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">23</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">completed</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Diabetes Mellitus</td><td align="center" valign="middle" rowspan="1" colspan="1">NCT01295073</td><td align="center" valign="middle" rowspan="1" colspan="1">II</td><td align="center" valign="middle" rowspan="1" colspan="1">0</td><td align="center" valign="middle" rowspan="1" colspan="1">TETA</td><td align="center" valign="middle" rowspan="1" colspan="1">withdrawn</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01213888</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.a.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">TETA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">terminated</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: DPA: D-penicillamine; MSC: mesenchymal stem cells; n.a.: not available; NCT number: <uri>ClinicalTrials.gov</uri> Identifier; PBT2: 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol; TETA: trientine tetrahydrochloride; TM: tetrathiomolybdate; WTX101: bis-choline tetrathiomolybdate.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Italie</li></country></list><tree><noCountry><name sortKey="Di Rocco, Giuliana" sort="Di Rocco, Giuliana" uniqKey="Di Rocco G" first="Giuliana" last="Di Rocco">Giuliana Di Rocco</name><name sortKey="Toietta, Gabriele" sort="Toietta, Gabriele" uniqKey="Toietta G" first="Gabriele" last="Toietta">Gabriele Toietta</name></noCountry><country name="Italie"><noRegion><name sortKey="Baldari, Silvia" sort="Baldari, Silvia" uniqKey="Baldari S" first="Silvia" last="Baldari">Silvia Baldari</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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