Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters
Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. A library of natural products (NCI Natural Product set) was screened for com...
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description | Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology.
A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.
The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids. |
doi_str_mv | 10.1371/journal.pone.0007238 |
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A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.
The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0007238</identifier><identifier>PMID: 19798419</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alkaloids - pharmacology ; Animal models ; Animals ; Anthracyclines ; Antibiotics ; Antineoplastic Agents - pharmacology ; Apoptosis ; Ascochyta salicorniae ; Bax protein ; Biological Transport ; Cancer therapies ; Carcinoma - drug therapy ; Carcinoma - metabolism ; Caspase ; Cell culture ; Cell Line, Tumor ; Colon ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - metabolism ; Croton ; Cytochrome ; Cytochrome c ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA topoisomerase ; DNA topoisomerase (ATP-hydrolysing) ; Doxorubicin ; Drug discovery ; Drug Evaluation, Preclinical ; Drugs ; Efflux ; Etoposide ; FDA approval ; Gene expression ; Humans ; Inhibitors ; Material requirements planning ; MEDICIN ; MEDICINE ; Mice ; Mitochondria ; Mitoxantrone ; Natural products ; Neoplasm Transplantation ; Oncology ; Oncology/Gastrointestinal Cancers ; Oncology/Oncology Agents ; Pathology ; Pharmacology/Drug Development ; Pharmacology/Drug Resistance ; Phosphatase ; Plant Extracts - pharmacology ; Potassium ; Protein Conformation ; Proteins ; Spheroids ; Streptomyces ; Therapeutics ; Topoisomerase I Inhibitors ; Transcription factors ; Trees ; Xenografts</subject><ispartof>PloS one, 2009-10, Vol.4 (10), p.e7238-e7238</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Fayad et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (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>Fayad et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c800t-be06d35159cf983a65d715a5b3f6b47d1977fc5e2a668ad1ae93c4c5430ffe303</citedby><cites>FETCH-LOGICAL-c800t-be06d35159cf983a65d715a5b3f6b47d1977fc5e2a668ad1ae93c4c5430ffe303</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/PMC2749935/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749935/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,725,778,782,862,883,2098,2917,23849,27907,27908,53774,53776,79351,79352</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19798419$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-130314$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:119836671$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Blagosklonny, Mikhail V.</contributor><creatorcontrib>Fayad, Walid</creatorcontrib><creatorcontrib>Fryknäs, Mårten</creatorcontrib><creatorcontrib>Brnjic, Slavica</creatorcontrib><creatorcontrib>Olofsson, Maria Hägg</creatorcontrib><creatorcontrib>Larsson, Rolf</creatorcontrib><creatorcontrib>Linder, Stig</creatorcontrib><title>Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology.
A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.
The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.</description><subject>Alkaloids - pharmacology</subject><subject>Animal models</subject><subject>Animals</subject><subject>Anthracyclines</subject><subject>Antibiotics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Ascochyta salicorniae</subject><subject>Bax protein</subject><subject>Biological Transport</subject><subject>Cancer therapies</subject><subject>Carcinoma - drug therapy</subject><subject>Carcinoma - metabolism</subject><subject>Caspase</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Croton</subject><subject>Cytochrome</subject><subject>Cytochrome c</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA topoisomerase</subject><subject>DNA topoisomerase (ATP-hydrolysing)</subject><subject>Doxorubicin</subject><subject>Drug discovery</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drugs</subject><subject>Efflux</subject><subject>Etoposide</subject><subject>FDA approval</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Material requirements planning</subject><subject>MEDICIN</subject><subject>MEDICINE</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitoxantrone</subject><subject>Natural products</subject><subject>Neoplasm Transplantation</subject><subject>Oncology</subject><subject>Oncology/Gastrointestinal Cancers</subject><subject>Oncology/Oncology Agents</subject><subject>Pathology</subject><subject>Pharmacology/Drug Development</subject><subject>Pharmacology/Drug Resistance</subject><subject>Phosphatase</subject><subject>Plant Extracts - pharmacology</subject><subject>Potassium</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Spheroids</subject><subject>Streptomyces</subject><subject>Therapeutics</subject><subject>Topoisomerase I Inhibitors</subject><subject>Transcription factors</subject><subject>Trees</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</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>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9uO0zAQhiMEYpeFN0AQCWkREi12HDvxDVK1nCqttBKHvbUcZ9y6pHHWdkp5e5w2QIsArXMRa_LNb89M_iR5jNEUkwK_WtnetbKZdraFKUKoyEh5JznFnGQTliFy92B_kjzwfoUQJSVj95MTzAte5pifJs28hjYYbZQMxrap1alMW7uBJg22s8bbNTjpITXt0lQmWJeC1qCC2QyxVEHT-DTyDradA-9Nu0hr1y8GrOm3aXCy9Z11AZx_mNzTsvHwaHyfJV_evf188WFyefV-fjG7nKgSoTCpALGaUEy50rwkktG6wFTSimhW5UUdb19oRSGTjJWyxhI4UbmiOUHxagSRs-TpXrdrrBdjo7zAGc8yXuAcR2K-J2orV6JzZi3dd2GlEbuAdQshXTCqAZHXvCw45lBpkmOQkjDQmEYVHRdRUWuy1_LfoOurI7Ux9DXuQNC4OIv8y3_yb8z1bHd63wscK8F5xF-PxfTVGmoVx-Vkc5R1_KU1S7GwG5EVOeeERoHno4CzNz34INbGD3OTLdjei4IQxktGs0ie_5fMcF5kOUe3AQmmuz4_-wP8-zSme2ohY8NNq20sRMWnhrVR8f_WJsZn8fCSElYMPXlxlBCZANuwkL33Yv7p4-3Zq-tj9vyAXYJswtLbph-s4Y_BfA8qZ713oH_NAyMx2PNnnWKwpxjtGdOeHM7yd9LoR_ID_8s5EA</recordid><startdate>20091002</startdate><enddate>20091002</enddate><creator>Fayad, Walid</creator><creator>Fryknäs, Mårten</creator><creator>Brnjic, Slavica</creator><creator>Olofsson, Maria Hägg</creator><creator>Larsson, Rolf</creator><creator>Linder, Stig</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>AEUYN</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>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>DF2</scope><scope>D8T</scope><scope>ZZAVC</scope><scope>DOA</scope></search><sort><creationdate>20091002</creationdate><title>Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters</title><author>Fayad, Walid ; Fryknäs, Mårten ; Brnjic, Slavica ; Olofsson, Maria Hägg ; Larsson, Rolf ; Linder, Stig</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c800t-be06d35159cf983a65d715a5b3f6b47d1977fc5e2a668ad1ae93c4c5430ffe303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Alkaloids - 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One of the disease areas where natural products are most frequently used as therapeutics is oncology.
A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.
The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19798419</pmid><doi>10.1371/journal.pone.0007238</doi><tpages>e7238</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2009-10, Vol.4 (10), p.e7238-e7238 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1292297141 |
source | MEDLINE; DOAJ Directory of Open Access Journals; SWEPUB Freely available online; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Alkaloids - pharmacology Animal models Animals Anthracyclines Antibiotics Antineoplastic Agents - pharmacology Apoptosis Ascochyta salicorniae Bax protein Biological Transport Cancer therapies Carcinoma - drug therapy Carcinoma - metabolism Caspase Cell culture Cell Line, Tumor Colon Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Croton Cytochrome Cytochrome c Cytotoxicity Deoxyribonucleic acid DNA DNA topoisomerase DNA topoisomerase (ATP-hydrolysing) Doxorubicin Drug discovery Drug Evaluation, Preclinical Drugs Efflux Etoposide FDA approval Gene expression Humans Inhibitors Material requirements planning MEDICIN MEDICINE Mice Mitochondria Mitoxantrone Natural products Neoplasm Transplantation Oncology Oncology/Gastrointestinal Cancers Oncology/Oncology Agents Pathology Pharmacology/Drug Development Pharmacology/Drug Resistance Phosphatase Plant Extracts - pharmacology Potassium Protein Conformation Proteins Spheroids Streptomyces Therapeutics Topoisomerase I Inhibitors Transcription factors Trees Xenografts |
title | Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters |
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