Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators
Identifieur interne : 000755 ( Pmc/Curation ); précédent : 000754; suivant : 000756Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators
Auteurs : Gang Cheng [États-Unis] ; Jacek Zielonka [États-Unis] ; Micael Hardy [France] ; Olivier Ouari [France] ; Christopher R. Chitambar [États-Unis] ; Michael B. Dwinell [États-Unis] ; Balaraman Kalyanaraman [États-Unis]Source :
- Oncotarget [ 1949-2553 ] ; 2019.
Abstract
We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signaling was proposed as a key mechanism for decreased cancer cell proliferation. Because of its poor bioavailability, the use of Met as a “stand-alone” antitumor drug has been questioned. Iron chelators such as deferasirox (DFX) and dexrazoxane (DXR) exhibit antiproliferative effects in cancer cells. The potency of Met and Mito-Met was synergistically enhanced in the presence of iron chelators, DFX, N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid (HBED), and deferoxamine (DFO). Met, DXR (also ICRF-187), and DFO are FDA-approved drugs for treating diabetes, decreasing the incidence and severity of cardiotoxicity following chemotherapy, and mitigating iron toxicity, respectively. Thus, the synergistic antiproliferative effects of Met and Met analogs and iron chelators may have significant clinical relevance in cancer treatment. These findings may have implications in other OXPHOS-mediated cancer therapies.
Url:
DOI: 10.18632/oncotarget.26943
PubMed: 31191823
PubMed Central: 6544408
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signaling was proposed as a key mechanism for decreased cancer cell proliferation. Because of its poor bioavailability, the use of Met as a “stand-alone” antitumor drug has been questioned. Iron chelators such as deferasirox (DFX) and dexrazoxane (DXR) exhibit antiproliferative effects in cancer cells. The potency of Met and Mito-Met was synergistically enhanced in the presence of iron chelators, DFX, N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid (HBED), and deferoxamine (DFO). Met, DXR (also ICRF-187), and DFO are FDA-approved drugs for treating diabetes, decreasing the incidence and severity of cardiotoxicity following chemotherapy, and mitigating iron toxicity, respectively. Thus, the synergistic antiproliferative effects of Met and Met analogs and iron chelators may have significant clinical relevance in cancer treatment. These findings may have implications in other OXPHOS-mediated cancer therapies.</p>
</div>
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<title-group><article-title>Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Cheng</surname>
<given-names>Gang</given-names>
</name>
<xref ref-type="aff" rid="A1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="A2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zielonka</surname>
<given-names>Jacek</given-names>
</name>
<xref ref-type="aff" rid="A1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="A2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="A3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hardy</surname>
<given-names>Micael</given-names>
</name>
<xref ref-type="aff" rid="A7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ouari</surname>
<given-names>Olivier</given-names>
</name>
<xref ref-type="aff" rid="A7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chitambar</surname>
<given-names>Christopher R.</given-names>
</name>
<xref ref-type="aff" rid="A1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="A4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dwinell</surname>
<given-names>Michael B.</given-names>
</name>
<xref ref-type="aff" rid="A3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="A5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="A6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kalyanaraman</surname>
<given-names>Balaraman</given-names>
</name>
<xref ref-type="corresp" rid="cor1"></xref>
<xref ref-type="aff" rid="A1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="A2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="A3"><sup>3</sup>
</xref>
</contrib>
<aff id="A1"><sup>1</sup>
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A2"><sup>2</sup>
Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A3"><sup>3</sup>
Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A4"><sup>4</sup>
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A5"><sup>5</sup>
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A6"><sup>6</sup>
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA</aff>
<aff id="A7"><sup>7</sup>
Aix Marseille University, CNRS, ICR, UMR 7273, Marseille 13013, France</aff>
</contrib-group>
<author-notes><corresp id="cor1"><bold><italic>Correspondence to: </italic>
</bold>
<italic>Balaraman Kalyanaraman</italic>
, <bold><italic>email</italic>
</bold>
: <email>balarama@mcw.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="collection"><day>28</day>
<month>5</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub"><day>28</day>
<month>5</month>
<year>2019</year>
</pub-date>
<volume>10</volume>
<issue>37</issue>
<fpage>3518</fpage>
<lpage>3532</lpage>
<history><date date-type="received"><day>21</day>
<month>3</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>02</day>
<month>5</month>
<year>2019</year>
</date>
</history>
<permissions><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p><bold>Copyright:</bold>
Cheng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<abstract><title>ABSTRACT</title>
<p>We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signaling was proposed as a key mechanism for decreased cancer cell proliferation. Because of its poor bioavailability, the use of Met as a “stand-alone” antitumor drug has been questioned. Iron chelators such as deferasirox (DFX) and dexrazoxane (DXR) exhibit antiproliferative effects in cancer cells. The potency of Met and Mito-Met was synergistically enhanced in the presence of iron chelators, DFX, N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid (HBED), and deferoxamine (DFO). Met, DXR (also ICRF-187), and DFO are FDA-approved drugs for treating diabetes, decreasing the incidence and severity of cardiotoxicity following chemotherapy, and mitigating iron toxicity, respectively. Thus, the synergistic antiproliferative effects of Met and Met analogs and iron chelators may have significant clinical relevance in cancer treatment. These findings may have implications in other OXPHOS-mediated cancer therapies.</p>
</abstract>
<kwd-group><kwd>iron chelators</kwd>
<kwd>mitochondria-targeting agents</kwd>
<kwd>cancer cell proliferation</kwd>
<kwd>biguanide; metformin analogs</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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