Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression
Identifieur interne : 000723 ( Pmc/Curation ); précédent : 000722; suivant : 000724Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression
Auteurs : Ikuko Nakamae ; Tsumoru Morimoto ; Hiroki Shima ; Masafumi Shionyu ; Hisayo Fujiki ; Noriko Yoneda-Kato ; Takashi Yokoyama ; Shigehiko Kanaya ; Kiyomi Kakiuchi ; Tsuyoshi Shirai ; Edy Meiyanto ; Jun-Ya KatoSource :
- Molecules [ 1420-3049 ] ; 2019.
Abstract
Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant,
Url:
DOI: 10.3390/molecules24224067
PubMed: 31717651
PubMed Central: 6891586
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<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
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<author><name sortKey="Morimoto, Tsumoru" sort="Morimoto, Tsumoru" uniqKey="Morimoto T" first="Tsumoru" last="Morimoto">Tsumoru Morimoto</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
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<author><name sortKey="Shima, Hiroki" sort="Shima, Hiroki" uniqKey="Shima H" first="Hiroki" last="Shima">Hiroki Shima</name>
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(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
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<author><name sortKey="Shionyu, Masafumi" sort="Shionyu, Masafumi" uniqKey="Shionyu M" first="Masafumi" last="Shionyu">Masafumi Shionyu</name>
<affiliation><nlm:aff id="af3-molecules-24-04067">Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan;<email>m_shionyu@nagahama-i-bio.ac.jp</email>
(M.S.);<email>t_shirai@nagahama-i-bio.ac.jp</email>
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<author><name sortKey="Fujiki, Hisayo" sort="Fujiki, Hisayo" uniqKey="Fujiki H" first="Hisayo" last="Fujiki">Hisayo Fujiki</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
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<author><name sortKey="Yoneda Kato, Noriko" sort="Yoneda Kato, Noriko" uniqKey="Yoneda Kato N" first="Noriko" last="Yoneda-Kato">Noriko Yoneda-Kato</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
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<author><name sortKey="Yokoyama, Takashi" sort="Yokoyama, Takashi" uniqKey="Yokoyama T" first="Takashi" last="Yokoyama">Takashi Yokoyama</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
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<author><name sortKey="Kanaya, Shigehiko" sort="Kanaya, Shigehiko" uniqKey="Kanaya S" first="Shigehiko" last="Kanaya">Shigehiko Kanaya</name>
<affiliation><nlm:aff id="af4-molecules-24-04067">Laboratory of Computational Systems Biology, Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>skanaya@gtc.naist.jp</email>
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<author><name sortKey="Kakiuchi, Kiyomi" sort="Kakiuchi, Kiyomi" uniqKey="Kakiuchi K" first="Kiyomi" last="Kakiuchi">Kiyomi Kakiuchi</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
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<author><name sortKey="Shirai, Tsuyoshi" sort="Shirai, Tsuyoshi" uniqKey="Shirai T" first="Tsuyoshi" last="Shirai">Tsuyoshi Shirai</name>
<affiliation><nlm:aff id="af3-molecules-24-04067">Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan;<email>m_shionyu@nagahama-i-bio.ac.jp</email>
(M.S.);<email>t_shirai@nagahama-i-bio.ac.jp</email>
(T.S.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meiyanto, Edy" sort="Meiyanto, Edy" uniqKey="Meiyanto E" first="Edy" last="Meiyanto">Edy Meiyanto</name>
<affiliation><nlm:aff id="af5-molecules-24-04067">Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia;<email>edy_meiyanto@ugm.ac.id</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kato, Jun Ya" sort="Kato, Jun Ya" uniqKey="Kato J" first="Jun-Ya" last="Kato">Jun-Ya Kato</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression</title>
<author><name sortKey="Nakamae, Ikuko" sort="Nakamae, Ikuko" uniqKey="Nakamae I" first="Ikuko" last="Nakamae">Ikuko Nakamae</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
(T.Y.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Morimoto, Tsumoru" sort="Morimoto, Tsumoru" uniqKey="Morimoto T" first="Tsumoru" last="Morimoto">Tsumoru Morimoto</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
(K.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shima, Hiroki" sort="Shima, Hiroki" uniqKey="Shima H" first="Hiroki" last="Shima">Hiroki Shima</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
(K.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shionyu, Masafumi" sort="Shionyu, Masafumi" uniqKey="Shionyu M" first="Masafumi" last="Shionyu">Masafumi Shionyu</name>
<affiliation><nlm:aff id="af3-molecules-24-04067">Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan;<email>m_shionyu@nagahama-i-bio.ac.jp</email>
(M.S.);<email>t_shirai@nagahama-i-bio.ac.jp</email>
(T.S.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fujiki, Hisayo" sort="Fujiki, Hisayo" uniqKey="Fujiki H" first="Hisayo" last="Fujiki">Hisayo Fujiki</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
(K.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yoneda Kato, Noriko" sort="Yoneda Kato, Noriko" uniqKey="Yoneda Kato N" first="Noriko" last="Yoneda-Kato">Noriko Yoneda-Kato</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
(T.Y.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yokoyama, Takashi" sort="Yokoyama, Takashi" uniqKey="Yokoyama T" first="Takashi" last="Yokoyama">Takashi Yokoyama</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
(T.Y.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kanaya, Shigehiko" sort="Kanaya, Shigehiko" uniqKey="Kanaya S" first="Shigehiko" last="Kanaya">Shigehiko Kanaya</name>
<affiliation><nlm:aff id="af4-molecules-24-04067">Laboratory of Computational Systems Biology, Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>skanaya@gtc.naist.jp</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kakiuchi, Kiyomi" sort="Kakiuchi, Kiyomi" uniqKey="Kakiuchi K" first="Kiyomi" last="Kakiuchi">Kiyomi Kakiuchi</name>
<affiliation><nlm:aff id="af2-molecules-24-04067">Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
(K.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shirai, Tsuyoshi" sort="Shirai, Tsuyoshi" uniqKey="Shirai T" first="Tsuyoshi" last="Shirai">Tsuyoshi Shirai</name>
<affiliation><nlm:aff id="af3-molecules-24-04067">Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan;<email>m_shionyu@nagahama-i-bio.ac.jp</email>
(M.S.);<email>t_shirai@nagahama-i-bio.ac.jp</email>
(T.S.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meiyanto, Edy" sort="Meiyanto, Edy" uniqKey="Meiyanto E" first="Edy" last="Meiyanto">Edy Meiyanto</name>
<affiliation><nlm:aff id="af5-molecules-24-04067">Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia;<email>edy_meiyanto@ugm.ac.id</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kato, Jun Ya" sort="Kato, Jun Ya" uniqKey="Kato J" first="Jun-Ya" last="Kato">Jun-Ya Kato</name>
<affiliation><nlm:aff id="af1-molecules-24-04067">Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
(T.Y.)</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Molecules</title>
<idno type="eISSN">1420-3049</idno>
<imprint><date when="2019">2019</date>
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<front><div type="abstract" xml:lang="en"><p>Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, <italic>N</italic>
-acetyl-cysteine (NAC). Some compounds exhibited lower GI<sub>50</sub>
values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities. Conclusions: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects.</p>
</div>
</front>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Molecules</journal-id>
<journal-id journal-id-type="iso-abbrev">Molecules</journal-id>
<journal-id journal-id-type="publisher-id">molecules</journal-id>
<journal-title-group><journal-title>Molecules</journal-title>
</journal-title-group>
<issn pub-type="epub">1420-3049</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31717651</article-id>
<article-id pub-id-type="pmc">6891586</article-id>
<article-id pub-id-type="doi">10.3390/molecules24224067</article-id>
<article-id pub-id-type="publisher-id">molecules-24-04067</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Nakamae</surname>
<given-names>Ikuko</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-24-04067">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1956-8777</contrib-id>
<name><surname>Morimoto</surname>
<given-names>Tsumoru</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-24-04067">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shima</surname>
<given-names>Hiroki</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-24-04067">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0431-3456</contrib-id>
<name><surname>Shionyu</surname>
<given-names>Masafumi</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-24-04067">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fujiki</surname>
<given-names>Hisayo</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-24-04067">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yoneda-Kato</surname>
<given-names>Noriko</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-24-04067">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yokoyama</surname>
<given-names>Takashi</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-24-04067">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kanaya</surname>
<given-names>Shigehiko</given-names>
</name>
<xref ref-type="aff" rid="af4-molecules-24-04067">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kakiuchi</surname>
<given-names>Kiyomi</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-24-04067">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2506-5738</contrib-id>
<name><surname>Shirai</surname>
<given-names>Tsuyoshi</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-24-04067">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Meiyanto</surname>
<given-names>Edy</given-names>
</name>
<xref ref-type="aff" rid="af5-molecules-24-04067">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kato</surname>
<given-names>Jun-ya</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-24-04067">1</xref>
<xref rid="c1-molecules-24-04067" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-molecules-24-04067"><label>1</label>
Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>ikuko-n@bs.naist.jp</email>
(I.N.);<email>noriko-k@bs.naist.jp</email>
(N.Y.-K.);<email>yokoyama-t@bs.naist.jp</email>
(T.Y.)</aff>
<aff id="af2-molecules-24-04067"><label>2</label>
Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>morimoto@ms.naist.jp</email>
(T.M.);<email>shima.hiroki.sz2@ms.naist.jp</email>
(H.S.);<email>f-hisayo@ad.naist.jp</email>
(H.F.);<email>kakiuchi@ms.naist.jp</email>
(K.K.)</aff>
<aff id="af3-molecules-24-04067"><label>3</label>
Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan;<email>m_shionyu@nagahama-i-bio.ac.jp</email>
(M.S.);<email>t_shirai@nagahama-i-bio.ac.jp</email>
(T.S.)</aff>
<aff id="af4-molecules-24-04067"><label>4</label>
Laboratory of Computational Systems Biology, Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan;<email>skanaya@gtc.naist.jp</email>
</aff>
<aff id="af5-molecules-24-04067"><label>5</label>
Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia;<email>edy_meiyanto@ugm.ac.id</email>
</aff>
<author-notes><corresp id="c1-molecules-24-04067"><label>*</label>
Correspondence: <email>jkata@bs.naist.jp</email>
; Tel.: +81-743-72-5510</corresp>
</author-notes>
<pub-date pub-type="epub"><day>10</day>
<month>11</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>11</month>
<year>2019</year>
</pub-date>
<volume>24</volume>
<issue>22</issue>
<elocation-id>4067</elocation-id>
<history><date date-type="received"><day>04</day>
<month>10</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>07</day>
<month>11</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</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>Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, <italic>N</italic>
-acetyl-cysteine (NAC). Some compounds exhibited lower GI<sub>50</sub>
values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities. Conclusions: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects.</p>
</abstract>
<kwd-group><kwd>curcumin</kwd>
<kwd>cancer</kwd>
<kwd>ROS</kwd>
<kwd>tumorigenicity</kwd>
<kwd>apoptosis</kwd>
<kwd>senescence</kwd>
<kwd>ROS metabolic enzymes</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="molecules-24-04067-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Chemical structure of curcumin and curcumin derivatives used in this study.</p>
</caption>
<graphic xlink:href="molecules-24-04067-g001"></graphic>
</fig>
<fig id="molecules-24-04067-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Growth inhibition by curcumin derivatives. (<bold>a</bold>
,<bold>b</bold>
) K562 cells (10<sup>5</sup>
cells/mL) were cultured in the presence of each compound (50 μM) for 4 days. Cells were enumerated every day using the trypan blue staining method. The results for viable (<bold>a</bold>
) and dead (<bold>b</bold>
) cells are shown. (<bold>c</bold>
) The GI<sub>50</sub>
of curcumin derivatives on K562 cells was determined after a 4-day culture. (<bold>d</bold>
) K562 cells (3 × 10<sup>5</sup>
cells/mL) were cultured in the presence of each compound for 2 days, washed once and transferred to the fresh medium without either compound. Viable cells were counted by the trypan blue exclusion method.</p>
</caption>
<graphic xlink:href="molecules-24-04067-g002a"></graphic>
<graphic xlink:href="molecules-24-04067-g002b"></graphic>
</fig>
<fig id="molecules-24-04067-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Growth inhibitory properties of curcumin derivatives. (<bold>a</bold>
) K562 cells (5 × 10<sup>5</sup>
cells/mL) were treated with curcumin derivatives (50 μM) for 2 and 4 days, and subjected to the cell cycle analysis. (<bold>b</bold>
) Cells treated as in (<bold>a</bold>
) were subjected to SA-β-gal staining. (<bold>c</bold>
) Cells treated with curcumin derivatives (50 μM) for 1 h (lower panel), 24, 48, and 72 h (upper panel) were subjected to a ROS detection analysis using FACS. (<bold>d</bold>
) Cells (3 × 10<sup>5</sup>
cells/mL) were cultured in the presence of each compound (50 μM) with and without NAC (5 mM and 10 mM) for 2 days, and viable cells were counted using the trypan blue staining method. HEPES buffer was supplemented to avoid a change in pH. (<bold>a</bold>
–<bold>d</bold>
) The results are the averages of three independent experiments (means ± SD).</p>
</caption>
<graphic xlink:href="molecules-24-04067-g003a"></graphic>
<graphic xlink:href="molecules-24-04067-g003b"></graphic>
<graphic xlink:href="molecules-24-04067-g003c"></graphic>
</fig>
<fig id="molecules-24-04067-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Inhibition of tumor formation by curcumin derivatives. (<bold>a</bold>
) K562 cells (2.5 × 10<sup>6</sup>
cells) were transplanted s.c. into the flanks of nude mice. Mice were then treated with curcumin derivatives (25 mg/kg BW) in corn oil and vehicle (corn oil) via an i.p. injection every 2 days. The tumor sizes were measured every 2 days. (<bold>b</bold>
–<bold>d</bold>
) After 18 days post-injection, mice were sacrificed, tumors were taken (<bold>b</bold>
), and tumor weights (<bold>c</bold>
) and the body weights (<bold>d</bold>
) were measured.</p>
</caption>
<graphic xlink:href="molecules-24-04067-g004a"></graphic>
<graphic xlink:href="molecules-24-04067-g004b"></graphic>
</fig>
<fig id="molecules-24-04067-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Cluster analysis. (<bold>a</bold>
) Heatmap of normalized 11 measurement variables obtained from 13 curcumin derivatives. The dendrograms on the top and left of the heatmap indicate the hierarchical clustering of the measurement variables and derivatives, respectively. The clustering analyses were performed by using complete linkage method with distance matrix converted from the correlation matrix of the normalized measurement variables. A threshold of 0.7× (maximum value of distance between the clusters) was employed for the clustering. The leaves of the dendrograms are colored according to the clusters. (<bold>b</bold>
) PCA biplot of measurement variables and derivatives. The red arrows are projections of the measurement variables onto the first two principal components. The names of the measurement variables are colored according to the clusters in plate a. The derivatives (blue points) classified into the same cluster are surrounded by a dashed circle colored according to the clusters in plate a. (<bold>c</bold>
) Comparison of the chemical structures of the derivatives. The atom alignment was generated by the COMPLIG program [<xref rid="B39-molecules-24-04067" ref-type="bibr">39</xref>
]. The derivatives are surrounded by rectangles colored according to the clusters in plate a. The characteristic moieties of clusters 1 and 4 are highlighted in the alignment and encircled in the formula. The atom numbers are labeled for curcumin and the characteristic moieties for simplicity.</p>
</caption>
<graphic xlink:href="molecules-24-04067-g005"></graphic>
</fig>
<fig id="molecules-24-04067-f006" orientation="portrait" position="float"><label>Figure 6</label>
<caption><p>Binding of curcumin derivatives to ROS metabolic enzymes. (<bold>a</bold>
,<bold>b</bold>
) Control, curcumin, and curcumin derivatives beads were subjected to a pull-down assay using cell lysates containing HA-CBR1, HA-GSTP1, HA-PRDX1, HA-NQO1, HA-AKR1C1, HA-NQO2, and HA-GLO1 proteins (<bold>a</bold>
). Bound proteins were visualized by immunoblotting, using an anti-HA antibody (<bold>b</bold>
). (<bold>c</bold>
) Summary of the results of panel b. The positive combination is marked as O. (<bold>d</bold>
) Heatmap of the binding result shown in panel c. The dendrograms on the top and left of the heatmap indicate the hierarchical clustering of the target proteins and derivatives, respectively.</p>
</caption>
<graphic xlink:href="molecules-24-04067-g006a"></graphic>
<graphic xlink:href="molecules-24-04067-g006b"></graphic>
</fig>
<fig id="molecules-24-04067-f007" orientation="portrait" position="float"><label>Figure 7</label>
<caption><p>Predicted binding sites of curcumin on ROS metabolic enzymes, (<bold>a</bold>
) CBR1, (<bold>b</bold>
) GST-P1, (<bold>c</bold>
) NQO1, (<bold>d</bold>
) PRDX1, (<bold>e</bold>
) AKR1C1, (<bold>f</bold>
) NQO2, and (<bold>g</bold>
) GLO1. The ROS metabolic enzymes are shown in the surface model. The residues are colored by maroon gradation according to their propensity for ligand binding. The bound co-enzymes (NADPH, FAD, and NADP) or substrate/substrate analog (GSH and NBC-GSH) are shown in sphere models colored in blue. (<bold>h</bold>
,<bold>i</bold>
) Competitive pulldown assay between cell lysates containing HA-CBR1 (<bold>h</bold>
)/HA-GSTP1 (<bold>i</bold>
) proteins and curcumin derivatives-beads in the presence and absence of 10 mM NADPH (<bold>h</bold>
) and 10 mM glutathione (<bold>i</bold>
). Bound proteins were visualized by immunoblotting, using an anti-HA antibody. (<bold>j</bold>
–<bold>m</bold>
) CBR1 (<bold>j</bold>
) and GST-P1 (<bold>l</bold>
) enzymatic activities was measured in vitro in the presence of curcumin derivatives. The IC<sub>50</sub>
of the compounds is shown as the mean ± SD (<italic>n</italic>
= 3). CBR1 (<bold>k</bold>
) and GST-P1 (<bold>m</bold>
) activities in the presence of curcumin derivatives (50 μM) are shown as the mean ± SD (<italic>n</italic>
= 3).</p>
</caption>
<graphic xlink:href="molecules-24-04067-g007a"></graphic>
<graphic xlink:href="molecules-24-04067-g007b"></graphic>
<graphic xlink:href="molecules-24-04067-g007c"></graphic>
</fig>
<table-wrap id="molecules-24-04067-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">molecules-24-04067-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>Measurement variables of selected curcumin derivatives.</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</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CLogP <sup>(1)</sup>
</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Growth Suppression <sup>(2)</sup>
</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Death <sup>(3)</sup>
</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">1/GI50 <sup>(4)</sup>
</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Washout Growth Suppression <sup>(5)</sup>
</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Tumor Suppression <sup>(6)</sup>
</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Curcumin</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.94</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.83</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.08</td>
<td align="center" valign="middle" rowspan="1" colspan="1">20.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100.00</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-031</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.59</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.83</td>
<td align="center" valign="middle" rowspan="1" colspan="1">11.80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">20.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">40.32</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-037</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.91</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">15.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.31</td>
<td align="center" valign="middle" rowspan="1" colspan="1">28.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">95.16</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-047</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−2.20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.07</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−99.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−179.29</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-054</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.81</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.08</td>
<td align="center" valign="middle" rowspan="1" colspan="1">15.20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.16</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-055</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.05</td>
<td align="center" valign="middle" rowspan="1" colspan="1">29.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">69.35</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-056</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.35</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−23.80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−98.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">85.48</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-057</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.32</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.11</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−21.20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">96.77</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-062</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.88</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.06</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−24.50</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−101.61</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-064</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.98</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.50</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.33</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.08</td>
<td align="center" valign="middle" rowspan="1" colspan="1">23.83</td>
<td align="center" valign="middle" rowspan="1" colspan="1">82.26</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-073</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.47</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−20.70</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.50</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">−101.00</td>
<td align="center" valign="middle" rowspan="1" colspan="1">17.74</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">hs-089</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.68</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.50</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.83</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.20</td>
<td align="center" valign="middle" rowspan="1" colspan="1">38.71</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">hs-140</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.65</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.50</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.83</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.06</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12.00</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">−206.45</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><sup>(1)</sup>
CLog P values were calculated with ChemDraw 16.0. <sup>(2)</sup>
Growth suppression: 10 [Cell growth values], Cell growth: 10<sup>5</sup>
cells/mL of K562 cells were cultured in the presence of the compounds, and, after 4 days, the cell concentration was determined and divided by 10<sup>4</sup>
, as shown in <xref ref-type="fig" rid="molecules-24-04067-f002">Figure 2</xref>
a and <xref ref-type="app" rid="app1-molecules-24-04067">Table S1</xref>
. <sup>(3)</sup>
Cell death: 10<sup>5</sup>
cells/mL of K562 cells were cultured in the presence of the compounds, and, after 4 days, dead cells were enumerated by the trypan blue exclusion method. The cell concentration was divided by 10<sup>4</sup>
, as shown in <xref ref-type="fig" rid="molecules-24-04067-f002">Figure 2</xref>
b and <xref ref-type="app" rid="app1-molecules-24-04067">Table S1</xref>
. <sup>(4)</sup>
1/GI<sub>50</sub>
: the reciprocal of GI<sub>50</sub>
(GI<sub>50</sub>
is shown in <xref ref-type="fig" rid="molecules-24-04067-f002">Figure 2</xref>
c and <xref ref-type="app" rid="app1-molecules-24-04067">Table S1</xref>
). <sup>(5)</sup>
Washout growth suppression: 30 [Washout growth values], Washout growth: 3 × 10<sup>5</sup>
cells/mL of K562 cells were cultured in the presence of the compounds for 2 days and, then, the compounds were removed from the medium. The cells were maintained in compound-free medium for 4 days and enumerated. The cell concentration was divided by 10<sup>4</sup>
, as shown in <xref ref-type="fig" rid="molecules-24-04067-f002">Figure 2</xref>
f and <xref ref-type="app" rid="app1-molecules-24-04067">Table S1</xref>
. <sup>(6)</sup>
Tumor suppression was calculated as ([control tumor size] − [sample tumor size])/[control tumor size] × 100.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
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