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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Veröffentlicht in:PloS one 2009-10, Vol.4 (10), p.e7238-e7238
Hauptverfasser: Fayad, Walid, Fryknäs, Mårten, Brnjic, Slavica, Olofsson, Maria Hägg, Larsson, Rolf, Linder, Stig
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container_issue 10
container_start_page e7238
container_title PloS one
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creator Fayad, Walid
Fryknäs, Mårten
Brnjic, Slavica
Olofsson, Maria Hägg
Larsson, Rolf
Linder, Stig
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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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Uppsala universitet</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</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>Fayad, Walid</au><au>Fryknäs, Mårten</au><au>Brnjic, Slavica</au><au>Olofsson, Maria Hägg</au><au>Larsson, Rolf</au><au>Linder, Stig</au><au>Blagosklonny, Mikhail V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-10-02</date><risdate>2009</risdate><volume>4</volume><issue>10</issue><spage>e7238</spage><epage>e7238</epage><pages>e7238-e7238</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</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>
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identifier ISSN: 1932-6203
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issn 1932-6203
1932-6203
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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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