Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells
Identifieur interne : 000E73 ( Ncbi/Merge ); précédent : 000E72; suivant : 000E74Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells
Auteurs : Amanda L. Kalen ; Brett A. Wagner ; Ehab H. Sarsour ; Maneesh G. Kumar ; Jessica L. Reedy ; Garry R. Buettner ; Nabin C. Barua ; Prabhat C. GoswamiSource :
- Antioxidants [ 2076-3921 ] ; 2020.
Abstract
This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head–neck, pancreas and skin cancer cells; 50% inhibition (IC50) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G1-phase, suggesting a G1 delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and γH2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H2DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with
Url:
DOI: 10.3390/antiox9020108
PubMed: 31991904
PubMed Central: 7070254
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells</title><author><name sortKey="Kalen, Amanda L" sort="Kalen, Amanda L" uniqKey="Kalen A" first="Amanda L." last="Kalen">Amanda L. Kalen</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Wagner, Brett A" sort="Wagner, Brett A" uniqKey="Wagner B" first="Brett A." last="Wagner">Brett A. Wagner</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Sarsour, Ehab H" sort="Sarsour, Ehab H" uniqKey="Sarsour E" first="Ehab H." last="Sarsour">Ehab H. Sarsour</name><affiliation><nlm:aff id="af2-antioxidants-09-00108">Department of Basic Sciences, Kansas City University of Medicine and Biosciences, Kansas City, MO 64106, USA;<email>esarsour@kcumb.edu</email></nlm:aff></affiliation></author><author><name sortKey="Kumar, Maneesh G" sort="Kumar, Maneesh G" uniqKey="Kumar M" first="Maneesh G." last="Kumar">Maneesh G. Kumar</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Reedy, Jessica L" sort="Reedy, Jessica L" uniqKey="Reedy J" first="Jessica L." last="Reedy">Jessica L. Reedy</name><affiliation><nlm:aff id="af3-antioxidants-09-00108">Radiation Oncology Branch, Center for Cancer Research, National Cancer Institutes of Health, Bethesda, MD 20892, USA;<email>jess.reedy@nih.gov</email></nlm:aff></affiliation></author><author><name sortKey="Buettner, Garry R" sort="Buettner, Garry R" uniqKey="Buettner G" first="Garry R." last="Buettner">Garry R. Buettner</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Barua, Nabin C" sort="Barua, Nabin C" uniqKey="Barua N" first="Nabin C." last="Barua">Nabin C. Barua</name><affiliation><nlm:aff id="af4-antioxidants-09-00108">Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006 Assam, India;<email>ncbarua2000@yahoo.co.in</email></nlm:aff></affiliation></author><author><name sortKey="Goswami, Prabhat C" sort="Goswami, Prabhat C" uniqKey="Goswami P" first="Prabhat C." last="Goswami">Prabhat C. Goswami</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31991904</idno><idno type="pmc">7070254</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070254</idno><idno type="RBID">PMC:7070254</idno><idno type="doi">10.3390/antiox9020108</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000411</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000411</idno><idno type="wicri:Area/Pmc/Curation">000411</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000411</idno><idno type="wicri:Area/Pmc/Checkpoint">000131</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000131</idno><idno type="wicri:Area/Ncbi/Merge">000E73</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells</title><author><name sortKey="Kalen, Amanda L" sort="Kalen, Amanda L" uniqKey="Kalen A" first="Amanda L." last="Kalen">Amanda L. Kalen</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Wagner, Brett A" sort="Wagner, Brett A" uniqKey="Wagner B" first="Brett A." last="Wagner">Brett A. Wagner</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Sarsour, Ehab H" sort="Sarsour, Ehab H" uniqKey="Sarsour E" first="Ehab H." last="Sarsour">Ehab H. Sarsour</name><affiliation><nlm:aff id="af2-antioxidants-09-00108">Department of Basic Sciences, Kansas City University of Medicine and Biosciences, Kansas City, MO 64106, USA;<email>esarsour@kcumb.edu</email></nlm:aff></affiliation></author><author><name sortKey="Kumar, Maneesh G" sort="Kumar, Maneesh G" uniqKey="Kumar M" first="Maneesh G." last="Kumar">Maneesh G. Kumar</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Reedy, Jessica L" sort="Reedy, Jessica L" uniqKey="Reedy J" first="Jessica L." last="Reedy">Jessica L. Reedy</name><affiliation><nlm:aff id="af3-antioxidants-09-00108">Radiation Oncology Branch, Center for Cancer Research, National Cancer Institutes of Health, Bethesda, MD 20892, USA;<email>jess.reedy@nih.gov</email></nlm:aff></affiliation></author><author><name sortKey="Buettner, Garry R" sort="Buettner, Garry R" uniqKey="Buettner G" first="Garry R." last="Buettner">Garry R. Buettner</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author><author><name sortKey="Barua, Nabin C" sort="Barua, Nabin C" uniqKey="Barua N" first="Nabin C." last="Barua">Nabin C. Barua</name><affiliation><nlm:aff id="af4-antioxidants-09-00108">Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006 Assam, India;<email>ncbarua2000@yahoo.co.in</email></nlm:aff></affiliation></author><author><name sortKey="Goswami, Prabhat C" sort="Goswami, Prabhat C" uniqKey="Goswami P" first="Prabhat C." last="Goswami">Prabhat C. Goswami</name><affiliation><nlm:aff id="af1-antioxidants-09-00108">Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</nlm:aff></affiliation></author></analytic><series><title level="j">Antioxidants</title><idno type="eISSN">2076-3921</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>This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head–neck, pancreas and skin cancer cells; 50% inhibition (IC<sub>50</sub>) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G<sub>1</sub>-phase, suggesting a G<sub>1</sub> delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and γH2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H<sub>2</sub>DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with <italic>N</italic>-acetyl-<sc>l</sc>-cysteine and antioxidant enzymes (superoxide dismutase and catalase) significantly suppressed AG-1-induced toxicity, suggesting that superoxide and hydrogen peroxide contribute to AG-1-induced toxicity in human cancer cells. AG-1 represents a novel class of anti-cancer drug that is more potent than its parent compound, artemisinin. </p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Tu, Y" uniqKey="Tu Y">Y. Tu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chaturvedi, D" uniqKey="Chaturvedi D">D. Chaturvedi</name></author><author><name sortKey="Goswami, A" uniqKey="Goswami A">A. Goswami</name></author><author><name sortKey="Saikia, P P" uniqKey="Saikia P">P.P. Saikia</name></author><author><name sortKey="Barua, N C" uniqKey="Barua N">N.C. Barua</name></author><author><name sortKey="Rao, P G" uniqKey="Rao P">P.G. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antioxidants (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Antioxidants (Basel)</journal-id><journal-id journal-id-type="publisher-id">antioxidants</journal-id><journal-title-group><journal-title>Antioxidants</journal-title></journal-title-group><issn pub-type="epub">2076-3921</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31991904</article-id><article-id pub-id-type="pmc">7070254</article-id><article-id pub-id-type="doi">10.3390/antiox9020108</article-id><article-id pub-id-type="publisher-id">antioxidants-09-00108</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kalen</surname><given-names>Amanda L.</given-names></name><xref ref-type="aff" rid="af1-antioxidants-09-00108">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0094-7259</contrib-id><name><surname>Wagner</surname><given-names>Brett A.</given-names></name><xref ref-type="aff" rid="af1-antioxidants-09-00108">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-9384-5509</contrib-id><name><surname>Sarsour</surname><given-names>Ehab H.</given-names></name><xref ref-type="aff" rid="af2-antioxidants-09-00108">2</xref></contrib><contrib contrib-type="author"><name><surname>Kumar</surname><given-names>Maneesh G.</given-names></name><xref ref-type="aff" rid="af1-antioxidants-09-00108">1</xref></contrib><contrib contrib-type="author"><name><surname>Reedy</surname><given-names>Jessica L.</given-names></name><xref ref-type="aff" rid="af3-antioxidants-09-00108">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-5594-1903</contrib-id><name><surname>Buettner</surname><given-names>Garry R.</given-names></name><xref ref-type="aff" rid="af1-antioxidants-09-00108">1</xref></contrib><contrib contrib-type="author"><name><surname>Barua</surname><given-names>Nabin C.</given-names></name><xref ref-type="aff" rid="af4-antioxidants-09-00108">4</xref></contrib><contrib contrib-type="author"><name><surname>Goswami</surname><given-names>Prabhat C.</given-names></name><xref ref-type="aff" rid="af1-antioxidants-09-00108">1</xref><xref rid="c1-antioxidants-09-00108" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-antioxidants-09-00108"><label>1</label>Free Radical and Radiation Biology Division, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA;<email>amanda-kalen@uiowa.edu</email> (A.L.K.);<email>brett-wagner@uiowa.edu</email> (B.A.W.);<email>mgkumar@gmail.com</email> (M.G.K.);<email>garry-buettner@uiowa.edu</email> (G.R.B.)</aff><aff id="af2-antioxidants-09-00108"><label>2</label>Department of Basic Sciences, Kansas City University of Medicine and Biosciences, Kansas City, MO 64106, USA;<email>esarsour@kcumb.edu</email></aff><aff id="af3-antioxidants-09-00108"><label>3</label>Radiation Oncology Branch, Center for Cancer Research, National Cancer Institutes of Health, Bethesda, MD 20892, USA;<email>jess.reedy@nih.gov</email></aff><aff id="af4-antioxidants-09-00108"><label>4</label>Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006 Assam, India;<email>ncbarua2000@yahoo.co.in</email></aff><author-notes><corresp id="c1-antioxidants-09-00108"><label>*</label>Correspondence: <email>prabhat-goswami@uiowa.edu</email>; Tel.: +1-319-384-4666</corresp></author-notes><pub-date pub-type="epub"><day>26</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>2</month><year>2020</year></pub-date><volume>9</volume><issue>2</issue><elocation-id>108</elocation-id><history><date date-type="received"><day>13</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>24</day><month>1</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>This study used a nitroaliphatic chemistry approach to synthesize a novel artemisinin-derived carba-dimer (AG-1) and determined its anti-proliferative effects in human normal and cancer cells. AG-1 treatments selectively inhibit proliferation of cancer cells compared to normal human fibroblasts. Compared to artemisinin, AG-1 is more toxic to human breast, prostate, head–neck, pancreas and skin cancer cells; 50% inhibition (IC<sub>50</sub>) 123 µM in AG-1 vs. 290 µM in artemisinin-treated breast cancer cells. AG-1 treatment decreased (~5 folds) cyclin D1 protein expression that correlated with an increase in the percentage of cells in the G<sub>1</sub>-phase, suggesting a G<sub>1</sub> delay. AG-1-induced toxicity was independent of the DNA damage at 72 h post-treatment, as measured by micronuclei frequency and γH2AX protein levels. Results from electron paramagnetic resonance spectroscopy showed Fe-catalyzed formation of AG-1 carbon-centered radicals in a cell-free system. Flow cytometry analysis of H<sub>2</sub>DCF-DA oxidation showed a significant increase in the steady-state levels of reactive oxygen species (ROS) in AG-1-treated cells. Pre-treatment with <italic>N</italic>-acetyl-<sc>l</sc>-cysteine and antioxidant enzymes (superoxide dismutase and catalase) significantly suppressed AG-1-induced toxicity, suggesting that superoxide and hydrogen peroxide contribute to AG-1-induced toxicity in human cancer cells. AG-1 represents a novel class of anti-cancer drug that is more potent than its parent compound, artemisinin. </p></abstract><kwd-group><kwd>artemisinin</kwd><kwd>carba-dimer</kwd><kwd>aliphatic nitro chemistry</kwd><kwd>oxidative stress</kwd><kwd>cyclin D1</kwd></kwd-group></article-meta></front><floats-group><fig id="antioxidants-09-00108-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Synthesis of artemisinin-derived C-16 carba-dimer, AG-1. Nitroaliphatic chemistry was used to synthesize AG-1. (<bold>A</bold>) Artemisinin; (<bold>B</bold>) Artemisitene; (<bold>C</bold>) Scheme-1 for the synthesis of artemisinin-derived Michael adduct; <bold>(D)</bold> Scheme-2 for the artemisinin-derived C-16 carba-dimer, AG-1.</p></caption><graphic xlink:href="antioxidants-09-00108-g001"></graphic></fig><fig id="antioxidants-09-00108-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Artemisinin dimer (AG-1) treatment inhibits proliferation of MB-231 human mammary epithelial cancer cells. (<bold>A</bold>) Artemisinin (Art) dimer (AG-1) is more cytotoxic compared to Art. Twenty-four hours of asynchronous cultures of MB-231 were treated with 10 and 50 µM of Art or AG-1. Cells were continued in culture in the presence of the drug and cell numbers were counted at the time of addition of the drug (0 day) and then at 2 day intervals. Results are shown as average and standard deviation. Asterisks represent significance compared to untreated control cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05. (<bold>B</bold>) A significant decrease in IC<sub>50</sub> of AG-1 compared to Art-treated MB-231 cells. Cells were treated with 10-200 µM of Art or AG-1 and cell-number was counted at 72 hours after addition of the drug. Linear regression plot was used to calculate dose that resulted in 50% or more inhibition in cellular proliferation (IC<sub>50</sub>).</p></caption><graphic xlink:href="antioxidants-09-00108-g002"></graphic></fig><fig id="antioxidants-09-00108-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Artemisinin dimer (AG-1) treatments differentially inhibit proliferation of cancer vs. normal cells. Monolayer cultures of (<bold>A</bold>) Cal27 human head–neck cancer cells, (<bold>B</bold>) A375 human melanoma cells and (<bold>C</bold>) normal human fibroblasts (NHFs) were treated with 100 µM of Art and AG-1. Cell numbers were counted at 48–96 hours post-treatment. Asterisks represent significance compared to cell numbers in untreated control cells, <italic>n</italic> = 3, <italic>p</italic> < 0.05.</p></caption><graphic xlink:href="antioxidants-09-00108-g003"></graphic></fig><fig id="antioxidants-09-00108-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Artemisinin dimer (AG-1) treatment decreases cyclin D1 protein expression resulting in an increase in the percentage of cells in the G<sub>1</sub>-phase of the cell cycle. Exponentially growing asynchronous cultures of MB-231 cells were treated for 72 hours with 10–200 µM of Art or AG-1. Ethanol-fixed cells were treated with RNase A and propidium iodide (PI). Flow cytometry was used to measure DNA content of cells. The percentage of cells in the (<bold>A</bold>) G<sub>1</sub>-phase and (<bold>B</bold>) S + G<sub>2</sub> + M phases was calculated using MODFIT software. Results are presented as average and standard deviation. Asterisks represent significance compared to untreated control cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05. (<bold>C</bold>) Western blot analysis of cyclin D1 protein expression in Art- and AG-1-treated MB231 cells.</p></caption><graphic xlink:href="antioxidants-09-00108-g004"></graphic></fig><fig id="antioxidants-09-00108-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Artemisinin dimer (AG-1) treatment is more cytotoxic than Art. Asynchronous cultures of human (<bold>A</bold>) MB-231 breast cancer, (<bold>B</bold>) PC-3 prostate cancer and (<bold>C</bold>) MD-435 melanoma cancer cells were treated for 72 hours with Art or AG-1. Monolayer cultures were trypsinized and re-plated at limiting dilutions designed to plate single cells. Cultures were continued for 14 days in absence of the drugs. Cells were fixed and stained with crystal violet. Surviving fraction was calculated after correction for plating efficiency. Results are presented as average and standard deviation. Asterisks represent significance compared to untreated control cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05.</p></caption><graphic xlink:href="antioxidants-09-00108-g005"></graphic></fig><fig id="antioxidants-09-00108-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Artemisinin dimer (AG-1)-induced cytotoxicity appears to be independent of DNA damage measured at 72 hours post-treatment. (<bold>A</bold>) AG-1 and Art treatments did not cause any significant change in the percentage of micronuclei. Asynchronous cultures of MB-231 cells were treated for 72 hours with 50–200 µM of Art or AG-1 and then incubated with cytochalasin-B followed by staining with acridine orange. Micronuclei in binucleated cells with well-preserved cytoplasm were scored using microscopy. (<bold>B</bold>) AG-1 and Art treatments did not cause any significant change in the levels of phosphorylated H2AX (γH2AX). Total cellular protein extracts isolated from 72 hours control, Art- and AG-1-treated cells were separated by SDS-PAGE and transferred onto a nitrocellulose membrane. The membrane was then incubated with antibodies to γH2AX and actin.</p></caption><graphic xlink:href="antioxidants-09-00108-g006"></graphic></fig><fig id="antioxidants-09-00108-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Artemisinin dimer (AG-1) generates carbon-centered radicals in cell-free system, and it increases the steady-state levels of cellular reactive oxygen species (ROS). (<bold>A</bold>) Detection of AG-1 derived carbon-centered radicals in cell-free system. AG-1 (1 mM) was incubated in phosphate buffer saline (pH 7.4) containing 25 mM POBN (α-(4-pyridyl-1-oxide)-<italic>N</italic>-<italic>tert</italic>-butylnitrone) in the presence of 20 µM or 100 µM ferrous sulfate. EPR (Electron Paramagnetic Resonance) spectra have the characteristics of spin adducts of two different carbon-centered radicals (radical-1, a<sup>N</sup> = 16.0 G, a<sup>H</sup> = 2.8 G; radical-2, a<sup>N</sup> = 14.7 G, a<sup>H</sup> = 2.4 G with a g-shift of about 0.25 G and a concentration ratio close to 1:1). Representative spectra showing AG-1 derived carbon-centered radicals are shown. (<bold>B</bold>) Bar graph represents relative abundance of carbon-centered radicals in the presence of low (20 µM) and high (100 µM) concentrations of ferrous sulfate. (<bold>C</bold>) AG-1 treatment increases the intracellular flux of oxidants. MB-231 cells were treated with 50 µM of Art or AG-1 for 15 minutes and then incubated with H<sub>2</sub>DCF-DA (5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate). H<sub>2</sub>DCF-oxidation, i.e., formation of DCF, was measured by flow cytometry and percent change in MFI (Mean Fluorescence Intensity) was calculated relative to untreated controls for individual treatments. Results are presented as average and standard deviation. Asterisks represent significance compared to Art-treated cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05.</p></caption><graphic xlink:href="antioxidants-09-00108-g007"></graphic></fig><fig id="antioxidants-09-00108-f008" orientation="portrait" position="float"><label>Figure 8</label><caption><p>Higher glucose uptake in artemisinin dimer (AG-1)-treated human cancer cells. Asynchronous cultures of (<bold>A,D</bold>) A375 melanoma, (<bold>B,E</bold>) Cal27 head–neck and (<bold>C,F</bold>) MB-231 breast cancer cells were treated with 100 µM Art or AG-1 for 24 hours. Cells were rinsed and incubated with DMEM (Dulbecco’s Modified Eagles Media) containing 20 µM of 2-NBDG (2-(<italic>N</italic>-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose) for 1 hour. 2-NBDG fluorescence was measured using flow cytometry. (<bold>A–C</bold>) show representative flow cytometry histograms and quantitative data are shown in (<bold>D–F</bold>). Asterisks represent significance compared to untreated control cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05.</p></caption><graphic xlink:href="antioxidants-09-00108-g008"></graphic></fig><fig id="antioxidants-09-00108-f009" orientation="portrait" position="float"><label>Figure 9</label><caption><p>Oxidative stress regulates artemisinin dimer (AG-1)-induced cytotoxicity. (<bold>A</bold>) Pre-treatment with a thiol-antioxidant suppresses AG-1-induced cytotoxicity. Asynchronous cultures of MB-231 cells were pre-treated for 3 hours with 5 mM NAC (N-Acetyl-L-Cysteine) and then treated for 72 hours with 200 µM of AG-1. (<bold>B</bold>) Antioxidant enzymes inhibit AG-1-induced cytotoxicity. Asynchronous cultures of MB-231 cells were pre-treated for 3 hours with polyethylene glycol conjugated catalase (500 units mL<sup>−1</sup>) and superoxide dismutase (50 units mL<sup>−1</sup>) and then incubated with 200 µM of AG-1. (<bold>C</bold>) MIA PaCa-2 cells were treated with 5 mM NAC 3 hours prior to treatment with 5 µM AG-1. A clonogenic assay was used to measure cytotoxicity. Asterisks represent significance compared to untreated control cells; <italic>n</italic> = 3, <italic>p</italic> < 0.05. Ampersand (&) represents significance compared to cells that were treated with AG-1.</p></caption><graphic xlink:href="antioxidants-09-00108-g009"></graphic></fig><fig id="antioxidants-09-00108-f010" orientation="portrait" position="float"><label>Figure 10</label><caption><p>Pathways of artemisinin (<bold>A</bold>) carbon and (<bold>B</bold>) oxygen centered radical formation in cell-free system.</p></caption><graphic xlink:href="antioxidants-09-00108-g010"></graphic></fig><fig id="antioxidants-09-00108-f011" orientation="portrait" position="float"><label>Figure 11</label><caption><p>An illustration of AG-1 inducing oxidative stress and G<sub>1</sub> delay resulting in toxicity.</p></caption><graphic xlink:href="antioxidants-09-00108-g011"></graphic></fig></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Barua, Nabin C" sort="Barua, Nabin C" uniqKey="Barua N" first="Nabin C." last="Barua">Nabin C. Barua</name><name sortKey="Buettner, Garry R" sort="Buettner, Garry R" uniqKey="Buettner G" first="Garry R." last="Buettner">Garry R. Buettner</name><name sortKey="Goswami, Prabhat C" sort="Goswami, Prabhat C" uniqKey="Goswami P" first="Prabhat C." last="Goswami">Prabhat C. Goswami</name><name sortKey="Kalen, Amanda L" sort="Kalen, Amanda L" uniqKey="Kalen A" first="Amanda L." last="Kalen">Amanda L. Kalen</name><name sortKey="Kumar, Maneesh G" sort="Kumar, Maneesh G" uniqKey="Kumar M" first="Maneesh G." last="Kumar">Maneesh G. Kumar</name><name sortKey="Reedy, Jessica L" sort="Reedy, Jessica L" uniqKey="Reedy J" first="Jessica L." last="Reedy">Jessica L. Reedy</name><name sortKey="Sarsour, Ehab H" sort="Sarsour, Ehab H" uniqKey="Sarsour E" first="Ehab H." last="Sarsour">Ehab H. Sarsour</name><name sortKey="Wagner, Brett A" sort="Wagner, Brett A" uniqKey="Wagner B" first="Brett A." last="Wagner">Brett A. 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