Benzoxazole Derivative K313 Induces Cell Cycle Arrest, Apoptosis and Autophagy Blockage and Suppresses mTOR/p70S6K Pathway in Nalm-6 and Daudi Cells
Identifieur interne : 000189 ( Pmc/Checkpoint ); précédent : 000188; suivant : 000190Benzoxazole Derivative K313 Induces Cell Cycle Arrest, Apoptosis and Autophagy Blockage and Suppresses mTOR/p70S6K Pathway in Nalm-6 and Daudi Cells
Auteurs : Wenying Zhong ; Xinwen Tang ; Yang Liu ; Chunyu Zhou ; Pan Liu ; Enhui Li ; Peilin Zhong ; Haoxue Lv ; Qiang Zou ; Maolin WangSource :
- Molecules [ 1420-3049 ] ; 2020.
Abstract
Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.
Url:
DOI: 10.3390/molecules25040971
PubMed: 32098126
PubMed Central: 7070478
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Benzoxazole Derivative K313 Induces Cell Cycle Arrest, Apoptosis and Autophagy Blockage and Suppresses mTOR/p70S6K Pathway in Nalm-6 and Daudi Cells</title>
<author><name sortKey="Zhong, Wenying" sort="Zhong, Wenying" uniqKey="Zhong W" first="Wenying" last="Zhong">Wenying Zhong</name>
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<author><name sortKey="Tang, Xinwen" sort="Tang, Xinwen" uniqKey="Tang X" first="Xinwen" last="Tang">Xinwen Tang</name>
<affiliation><nlm:aff id="af2-molecules-25-00971">Center of Science and Research, Chengdu Medical College, Chengdu 610513, China;<email>tangxinwei11@gmail.com</email>
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<author><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name>
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<author><name sortKey="Liu, Pan" sort="Liu, Pan" uniqKey="Liu P" first="Pan" last="Liu">Pan Liu</name>
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<author><name sortKey="Li, Enhui" sort="Li, Enhui" uniqKey="Li E" first="Enhui" last="Li">Enhui Li</name>
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<author><name sortKey="Zou, Qiang" sort="Zou, Qiang" uniqKey="Zou Q" first="Qiang" last="Zou">Qiang Zou</name>
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<author><name sortKey="Wang, Maolin" sort="Wang, Maolin" uniqKey="Wang M" first="Maolin" last="Wang">Maolin Wang</name>
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<front><div type="abstract" xml:lang="en"><p>Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.</p>
</div>
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</div1>
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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">32098126</article-id>
<article-id pub-id-type="pmc">7070478</article-id>
<article-id pub-id-type="doi">10.3390/molecules25040971</article-id>
<article-id pub-id-type="publisher-id">molecules-25-00971</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Benzoxazole Derivative K313 Induces Cell Cycle Arrest, Apoptosis and Autophagy Blockage and Suppresses mTOR/p70S6K Pathway in Nalm-6 and Daudi Cells</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zhong</surname>
<given-names>Wenying</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-25-00971">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tang</surname>
<given-names>Xinwen</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-25-00971">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Yang</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-25-00971">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Chunyu</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-25-00971">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Pan</given-names>
</name>
<xref ref-type="aff" rid="af4-molecules-25-00971">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Enhui</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-25-00971">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhong</surname>
<given-names>Peilin</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-25-00971">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lv</surname>
<given-names>Haoxue</given-names>
</name>
<xref ref-type="aff" rid="af3-molecules-25-00971">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zou</surname>
<given-names>Qiang</given-names>
</name>
<xref ref-type="aff" rid="af2-molecules-25-00971">2</xref>
<xref rid="c1-molecules-25-00971" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Maolin</given-names>
</name>
<xref ref-type="aff" rid="af1-molecules-25-00971">1</xref>
<xref rid="c1-molecules-25-00971" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-molecules-25-00971"><label>1</label>
Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China;<email>hh1234qwer1@163.com</email>
</aff>
<aff id="af2-molecules-25-00971"><label>2</label>
Center of Science and Research, Chengdu Medical College, Chengdu 610513, China;<email>tangxinwei11@gmail.com</email>
(X.T.);<email>scunn519@gmail.com</email>
(Y.L.)</aff>
<aff id="af3-molecules-25-00971"><label>3</label>
School of Pharmacy, Chengdu Medical College, Chengdu 610083, China;<email>chunyu532@foxmail.com</email>
(C.Z.);<email>CoooCaaa@163.com</email>
(E.L.);<email>zhongpeiling33@163.com</email>
(P.Z.);<email>lv1137641610@163.com</email>
(H.L.)</aff>
<aff id="af4-molecules-25-00971"><label>4</label>
College of Biological Science and Technology, Chengdu Medical College, Chengdu 610500, China;<email>liupan145@gmail.com</email>
</aff>
<author-notes><corresp id="c1-molecules-25-00971"><label>*</label>
Correspondence: <email>qiangzou99@gmail.com</email>
(Q.Z.); <email>mlwang@scu.edu.cn</email>
(M.W.); Tel.: +86-028-62739159 (Q.Z.); +86-028-85418776 (M.W.)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>21</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><month>2</month>
<year>2020</year>
</pub-date>
<volume>25</volume>
<issue>4</issue>
<elocation-id>971</elocation-id>
<history><date date-type="received"><day>26</day>
<month>1</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>18</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>Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.</p>
</abstract>
<kwd-group><kwd>K313</kwd>
<kwd>B-cell acute lymphoblastic leukemia</kwd>
<kwd>B-cell Burkitt’s lymphoma</kwd>
<kwd>cell cycle arrest</kwd>
<kwd>apoptosis</kwd>
<kwd>mitochondrial pathway</kwd>
<kwd>autophagy blockage</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Li, Enhui" sort="Li, Enhui" uniqKey="Li E" first="Enhui" last="Li">Enhui Li</name>
<name sortKey="Liu, Pan" sort="Liu, Pan" uniqKey="Liu P" first="Pan" last="Liu">Pan Liu</name>
<name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name>
<name sortKey="Lv, Haoxue" sort="Lv, Haoxue" uniqKey="Lv H" first="Haoxue" last="Lv">Haoxue Lv</name>
<name sortKey="Tang, Xinwen" sort="Tang, Xinwen" uniqKey="Tang X" first="Xinwen" last="Tang">Xinwen Tang</name>
<name sortKey="Wang, Maolin" sort="Wang, Maolin" uniqKey="Wang M" first="Maolin" last="Wang">Maolin Wang</name>
<name sortKey="Zhong, Peilin" sort="Zhong, Peilin" uniqKey="Zhong P" first="Peilin" last="Zhong">Peilin Zhong</name>
<name sortKey="Zhong, Wenying" sort="Zhong, Wenying" uniqKey="Zhong W" first="Wenying" last="Zhong">Wenying Zhong</name>
<name sortKey="Zhou, Chunyu" sort="Zhou, Chunyu" uniqKey="Zhou C" first="Chunyu" last="Zhou">Chunyu Zhou</name>
<name sortKey="Zou, Qiang" sort="Zou, Qiang" uniqKey="Zou Q" first="Qiang" last="Zou">Qiang Zou</name>
</noCountry>
</tree>
</affiliations>
</record>
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