Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes
Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a nove...
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| Veröffentlicht in: | PloS one 2012-11, Vol.7 (11), p.e50125 |
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| description | Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death. |
| doi_str_mv | 10.1371/journal.pone.0050125 |
| format | Article |
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In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0050125</identifier><identifier>PMID: 23185555</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Acrolein - analogs & derivatives ; Acrolein - chemical synthesis ; Acrolein - pharmacology ; Adenosine diphosphate ; Agglomeration ; Analogs ; Anticancer properties ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Antitumor agents ; Apoptosis ; Apoptosis - drug effects ; Benzoates - chemical synthesis ; Benzoates - pharmacology ; Biochemistry ; Biology ; Biotin ; Cancer therapies ; Caspase ; Caspase 3 - genetics ; Caspase 3 - metabolism ; Caspase-3 ; Cell adhesion ; Cell cycle ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell death ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Cell-free system ; Cellular communication ; Cinnamaldehyde ; Colon ; Cyclin B1 ; Drug interaction ; Drug interactions ; Fungal Proteins - genetics ; G2 phase ; G2 Phase Cell Cycle Checkpoints - drug effects ; Gene Expression - drug effects ; Histone H3 ; Histones - genetics ; Histones - metabolism ; Humans ; Medicine ; Mitosis ; Mortality ; Pharmaceuticals ; Pharmacy ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerases - genetics ; Poly(ADP-ribose) Polymerases - metabolism ; Polymerization ; Proteins ; Regulatory proteins ; Ribose ; Sulfhydryl groups ; Survivin ; Tubulin ; Tubulin - genetics ; Tubulin - metabolism ; Tumors ; Virulence Factors - genetics</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e50125</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Nagle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Nagle et al 2012 Nagle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-ff558cf66e34ec5b69a74a32731db7de5f9e01e56bf75424858e14fb1b1d722c3</citedby><cites>FETCH-LOGICAL-c692t-ff558cf66e34ec5b69a74a32731db7de5f9e01e56bf75424858e14fb1b1d722c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503761/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503761/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23185555$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lebedeva, Irina V.</contributor><creatorcontrib>Nagle, Amrita A</creatorcontrib><creatorcontrib>Gan, Fei-Fei</creatorcontrib><creatorcontrib>Jones, Gavin</creatorcontrib><creatorcontrib>So, Choon-Leng</creatorcontrib><creatorcontrib>Wells, Geoffrey</creatorcontrib><creatorcontrib>Chew, Eng-Hui</creatorcontrib><title>Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.</description><subject>Accumulation</subject><subject>Acrolein - analogs & derivatives</subject><subject>Acrolein - chemical synthesis</subject><subject>Acrolein - pharmacology</subject><subject>Adenosine diphosphate</subject><subject>Agglomeration</subject><subject>Analogs</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Benzoates - chemical synthesis</subject><subject>Benzoates - pharmacology</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Biotin</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>Caspase 3 - genetics</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase-3</subject><subject>Cell adhesion</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - antagonists & inhibitors</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell-free system</subject><subject>Cellular communication</subject><subject>Cinnamaldehyde</subject><subject>Colon</subject><subject>Cyclin B1</subject><subject>Drug interaction</subject><subject>Drug interactions</subject><subject>Fungal Proteins - genetics</subject><subject>G2 phase</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Gene Expression - drug effects</subject><subject>Histone H3</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Medicine</subject><subject>Mitosis</subject><subject>Mortality</subject><subject>Pharmaceuticals</subject><subject>Pharmacy</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerases - genetics</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Polymerization</subject><subject>Proteins</subject><subject>Regulatory proteins</subject><subject>Ribose</subject><subject>Sulfhydryl groups</subject><subject>Survivin</subject><subject>Tubulin</subject><subject>Tubulin - genetics</subject><subject>Tubulin - metabolism</subject><subject>Tumors</subject><subject>Virulence Factors - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9uKFDEQhhtR3HX1DUQbBMGLGTtJpw83wrJ4GFhY8HQb0jl0Z00nYw6L_SI-r5mZnmUaFEwuKlR99ScpqrLsOSjWANXg7a2NzlC93loj1kWBCwDxg-wctAiuKlighyfns-yJ97cJQk1VPc7OIAINTus8-70xPLKgrMmtzEMcrcuZ0DrngoYhD4OzsU-Wul4EZfqEdFErk1PDc3Fnf-x8fPJO9FHTo85egU1Mi3wOWDflW2eDUMbn3ZSPUQclo9lfTROsjKEj1VwMExf-afZIUu3Fs9leZN8-vP969Wl1ffNxc3V5vWJVC8NKSowbJqtKoFIw3FUtrUuKYI0A72ousGxFAQSuOlnjEpYNbgQoZQc6wGsIGbrIXh50t9p6MpfUE4BgVZdtUbeJ2BwIbukt2To1UjcRSxXZO6zrCXVBpa-SDnPMEWKsKUQJmWxZyVFRlbiVkGJaJ613822xGwVnwgRH9UJ0GTFqIL29IwgXqK5AEng1Czj7Mwof_vHkmeppepUy0iYxNirPyGVZ1wWGZbuj1n-h0uZiVCw1lVTJv0h4s0hITBC_Qk-j92Tz5fP_szffl-zrE3YQVIfBWx13neGXYHkAmbM-dZy8rxwoyG4mjtUgu5kg80yktBenVb9POg4B-gNWEgvQ</recordid><startdate>20121121</startdate><enddate>20121121</enddate><creator>Nagle, Amrita A</creator><creator>Gan, Fei-Fei</creator><creator>Jones, Gavin</creator><creator>So, Choon-Leng</creator><creator>Wells, Geoffrey</creator><creator>Chew, Eng-Hui</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20121121</creationdate><title>Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes</title><author>Nagle, Amrita A ; Gan, Fei-Fei ; Jones, Gavin ; So, Choon-Leng ; Wells, Geoffrey ; Chew, Eng-Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-ff558cf66e34ec5b69a74a32731db7de5f9e01e56bf75424858e14fb1b1d722c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Accumulation</topic><topic>Acrolein - 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genetics</topic><topic>G2 phase</topic><topic>G2 Phase Cell Cycle Checkpoints - drug effects</topic><topic>Gene Expression - drug effects</topic><topic>Histone H3</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Medicine</topic><topic>Mitosis</topic><topic>Mortality</topic><topic>Pharmaceuticals</topic><topic>Pharmacy</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Poly(ADP-ribose) Polymerases - genetics</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Polymerization</topic><topic>Proteins</topic><topic>Regulatory proteins</topic><topic>Ribose</topic><topic>Sulfhydryl groups</topic><topic>Survivin</topic><topic>Tubulin</topic><topic>Tubulin - genetics</topic><topic>Tubulin - metabolism</topic><topic>Tumors</topic><topic>Virulence Factors - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagle, Amrita A</creatorcontrib><creatorcontrib>Gan, Fei-Fei</creatorcontrib><creatorcontrib>Jones, Gavin</creatorcontrib><creatorcontrib>So, Choon-Leng</creatorcontrib><creatorcontrib>Wells, Geoffrey</creatorcontrib><creatorcontrib>Chew, Eng-Hui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagle, Amrita A</au><au>Gan, Fei-Fei</au><au>Jones, Gavin</au><au>So, Choon-Leng</au><au>Wells, Geoffrey</au><au>Chew, Eng-Hui</au><au>Lebedeva, Irina V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-11-21</date><risdate>2012</risdate><volume>7</volume><issue>11</issue><spage>e50125</spage><pages>e50125-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23185555</pmid><doi>10.1371/journal.pone.0050125</doi><tpages>e50125</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-11, Vol.7 (11), p.e50125 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326749079 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Accumulation Acrolein - analogs & derivatives Acrolein - chemical synthesis Acrolein - pharmacology Adenosine diphosphate Agglomeration Analogs Anticancer properties Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antitumor agents Apoptosis Apoptosis - drug effects Benzoates - chemical synthesis Benzoates - pharmacology Biochemistry Biology Biotin Cancer therapies Caspase Caspase 3 - genetics Caspase 3 - metabolism Caspase-3 Cell adhesion Cell cycle Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell death Cell growth Cell Line, Tumor Cell proliferation Cell-free system Cellular communication Cinnamaldehyde Colon Cyclin B1 Drug interaction Drug interactions Fungal Proteins - genetics G2 phase G2 Phase Cell Cycle Checkpoints - drug effects Gene Expression - drug effects Histone H3 Histones - genetics Histones - metabolism Humans Medicine Mitosis Mortality Pharmaceuticals Pharmacy Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Polymerization Proteins Regulatory proteins Ribose Sulfhydryl groups Survivin Tubulin Tubulin - genetics Tubulin - metabolism Tumors Virulence Factors - genetics |
| title | Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes |
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