Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin
Conventional cytostatic cancer treatments rarely result in the complete eradication of tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a spec...
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| description | Conventional cytostatic cancer treatments rarely result in the complete eradication of tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of tumor tissue. Genistein, fingolimod and betulin have already been described as active compounds in different types of cancer. Herein, we applied an integrated screening approach to characterize both their cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different B16 melanoma cell lines to a given extent, as revealed by an MTT assay, CFSE and DAPI staining. However, while genistein and fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice, betulin exhibited a lower cytotoxicity for BMDCs in comparison to the melanoma cells. Moreover, we could show for the first time, that only betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an antigen specific model system. This may overcome the immunosuppressive environment of a tumor and destroy tumor cells more effectively in vivo if the immune response is specific targeted against the tumor tissue by antigen-loaded dendritic cells. In summary, cytostatic agents, such as betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated cancer therapy. |
| doi_str_mv | 10.1371/journal.pone.0118802 |
| format | Article |
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Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of tumor tissue. Genistein, fingolimod and betulin have already been described as active compounds in different types of cancer. Herein, we applied an integrated screening approach to characterize both their cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different B16 melanoma cell lines to a given extent, as revealed by an MTT assay, CFSE and DAPI staining. However, while genistein and fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice, betulin exhibited a lower cytotoxicity for BMDCs in comparison to the melanoma cells. Moreover, we could show for the first time, that only betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an antigen specific model system. This may overcome the immunosuppressive environment of a tumor and destroy tumor cells more effectively in vivo if the immune response is specific targeted against the tumor tissue by antigen-loaded dendritic cells. In summary, cytostatic agents, such as betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated cancer therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0118802</identifier><identifier>PMID: 25756279</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adjuvants, Immunologic - pharmacology ; Analysis ; Animals ; Antigens ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis ; Apoptosis - drug effects ; Authorship ; Biocompatibility ; Bone marrow ; Cancer ; Cancer therapies ; Care and treatment ; Cell activation ; Cell culture ; Cell cycle ; Cell Proliferation - drug effects ; Cell survival ; Cell Survival - drug effects ; Chemotherapy ; Complications and side effects ; Cytochrome ; Cytokines ; Cytostatic agents ; Cytotoxicity ; Dendritic cells ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme-linked immunosorbent assay ; Female ; Fingolimod Hydrochloride - pharmacology ; Gene expression ; Genistein ; Genistein - pharmacology ; Health aspects ; Immune response ; Immune system ; Immunomodulation ; Immunosuppressive agents ; Immunotherapy ; Influence ; Interferon ; Interleukin 12 ; Interleukin 2 ; Isoflavones ; Kinases ; Lead compounds ; Ligands ; Lymphocytes ; Lymphocytes T ; Melanoma ; Melanoma, Experimental - drug therapy ; Melanoma, Experimental - immunology ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Pharmacology ; Pharmacy ; Prostate ; Proteins ; Recurrence (Disease) ; Risk factors ; Skin cancer ; Spleen ; Studies ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; Toll-like receptors ; Toxicity ; Toxicology ; Triterpenes - pharmacology ; Tumor cells ; Tumors ; Viability ; γ-Interferon</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0118802</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Pfarr et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2015 Pfarr et al 2015 Pfarr et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-e90e5235e7edd0165dfb289aa089367445f4db485ac7f6f0d97e27e0c16ddfab3</citedby><cites>FETCH-LOGICAL-c692t-e90e5235e7edd0165dfb289aa089367445f4db485ac7f6f0d97e27e0c16ddfab3</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/PMC4355578/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355578/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25756279$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Multhoff, Gabriele</contributor><creatorcontrib>Pfarr, Kathrin</creatorcontrib><creatorcontrib>Danciu, Corina</creatorcontrib><creatorcontrib>Arlt, Olga</creatorcontrib><creatorcontrib>Neske, Christina</creatorcontrib><creatorcontrib>Dehelean, Cristina</creatorcontrib><creatorcontrib>Pfeilschifter, Josef M</creatorcontrib><creatorcontrib>Radeke, Heinfried H</creatorcontrib><title>Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Conventional cytostatic cancer treatments rarely result in the complete eradication of tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of tumor tissue. Genistein, fingolimod and betulin have already been described as active compounds in different types of cancer. Herein, we applied an integrated screening approach to characterize both their cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different B16 melanoma cell lines to a given extent, as revealed by an MTT assay, CFSE and DAPI staining. However, while genistein and fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice, betulin exhibited a lower cytotoxicity for BMDCs in comparison to the melanoma cells. Moreover, we could show for the first time, that only betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an antigen specific model system. This may overcome the immunosuppressive environment of a tumor and destroy tumor cells more effectively in vivo if the immune response is specific targeted against the tumor tissue by antigen-loaded dendritic cells. In summary, cytostatic agents, such as betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated cancer therapy.</description><subject>Adjuvants, Immunologic - pharmacology</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antigens</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Authorship</subject><subject>Biocompatibility</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell survival</subject><subject>Cell Survival - drug effects</subject><subject>Chemotherapy</subject><subject>Complications and side effects</subject><subject>Cytochrome</subject><subject>Cytokines</subject><subject>Cytostatic agents</subject><subject>Cytotoxicity</subject><subject>Dendritic cells</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Fingolimod Hydrochloride - pharmacology</subject><subject>Gene expression</subject><subject>Genistein</subject><subject>Genistein - pharmacology</subject><subject>Health aspects</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Immunosuppressive agents</subject><subject>Immunotherapy</subject><subject>Influence</subject><subject>Interferon</subject><subject>Interleukin 12</subject><subject>Interleukin 2</subject><subject>Isoflavones</subject><subject>Kinases</subject><subject>Lead compounds</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Melanoma</subject><subject>Melanoma, Experimental - drug therapy</subject><subject>Melanoma, Experimental - immunology</subject><subject>Mice, Inbred C57BL</subject><subject>Neoplasm Transplantation</subject><subject>Pharmacology</subject><subject>Pharmacy</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Recurrence (Disease)</subject><subject>Risk factors</subject><subject>Skin cancer</subject><subject>Spleen</subject><subject>Studies</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>Toll-like receptors</subject><subject>Toxicity</subject><subject>Toxicology</subject><subject>Triterpenes - pharmacology</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Viability</subject><subject>γ-Interferon</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNqNkl1rFDEYhQdRbK3-A9EBQfBi13xMksmNUIofC4WCVe8kZJN3drPMJNtJpnT_vdnutOyAguQi4c1zTsLhFMVrjOaYCvxxE4be63a-DR7mCOO6RuRJcYolJTNOEH16dD4pXsS4QYjRmvPnxQlhgnEi5Gnx-9p1Q5u0hzDEUntb2hChtLAFb8GnsoNW-9Dp0uxSSOHOmXvKdd3goYxpL9cp9LtSm-RuXdqVoSmXkIbW-ZfFs0a3EV6N-1nx88vnHxffZpdXXxcX55czwyVJM5AIGKEMBFiLMGe2WZJaao1qSbmoKtZUdlnVTBvR8AZZKYAIQAZzaxu9pGfF24Pvtg1RjclEhTnHss4eLBOLA2GD3qht7zrd71TQTt0PQr9Suk_OtKBYJWVWYYErU1FtJcWg5dJQSzilAmWvT-Nrw7IDa3JMvW4nptMb79ZqFW5VRRljos4G70aDPtwMENM_vjxSK51_5XwTspnpXDTqvCKc1bymIlPzv1B5Weicyd1oXJ5PBB8mgswkuEsrPcSoFtff_5-9-jVl3x-xa9BtWsfQDskFH6dgdQBNH2LsoXlMDiO1r_ZDGmpfbTVWO8veHKf-KHroMv0DVy_1eA</recordid><startdate>20150310</startdate><enddate>20150310</enddate><creator>Pfarr, Kathrin</creator><creator>Danciu, Corina</creator><creator>Arlt, Olga</creator><creator>Neske, Christina</creator><creator>Dehelean, Cristina</creator><creator>Pfeilschifter, Josef M</creator><creator>Radeke, Heinfried H</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>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150310</creationdate><title>Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin</title><author>Pfarr, Kathrin ; Danciu, Corina ; Arlt, Olga ; Neske, Christina ; Dehelean, Cristina ; Pfeilschifter, Josef M ; Radeke, Heinfried H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-e90e5235e7edd0165dfb289aa089367445f4db485ac7f6f0d97e27e0c16ddfab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adjuvants, Immunologic - 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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>Publicly Available Content Database</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>Pfarr, Kathrin</au><au>Danciu, Corina</au><au>Arlt, Olga</au><au>Neske, Christina</au><au>Dehelean, Cristina</au><au>Pfeilschifter, Josef M</au><au>Radeke, Heinfried H</au><au>Multhoff, Gabriele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-10</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0118802</spage><pages>e0118802-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Conventional cytostatic cancer treatments rarely result in the complete eradication of tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of tumor tissue. Genistein, fingolimod and betulin have already been described as active compounds in different types of cancer. Herein, we applied an integrated screening approach to characterize both their cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different B16 melanoma cell lines to a given extent, as revealed by an MTT assay, CFSE and DAPI staining. However, while genistein and fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice, betulin exhibited a lower cytotoxicity for BMDCs in comparison to the melanoma cells. Moreover, we could show for the first time, that only betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an antigen specific model system. This may overcome the immunosuppressive environment of a tumor and destroy tumor cells more effectively in vivo if the immune response is specific targeted against the tumor tissue by antigen-loaded dendritic cells. In summary, cytostatic agents, such as betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated cancer therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25756279</pmid><doi>10.1371/journal.pone.0118802</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-03, Vol.10 (3), p.e0118802 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1661988935 |
| 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 | Adjuvants, Immunologic - pharmacology Analysis Animals Antigens Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Apoptosis - drug effects Authorship Biocompatibility Bone marrow Cancer Cancer therapies Care and treatment Cell activation Cell culture Cell cycle Cell Proliferation - drug effects Cell survival Cell Survival - drug effects Chemotherapy Complications and side effects Cytochrome Cytokines Cytostatic agents Cytotoxicity Dendritic cells Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Enzyme-linked immunosorbent assay Female Fingolimod Hydrochloride - pharmacology Gene expression Genistein Genistein - pharmacology Health aspects Immune response Immune system Immunomodulation Immunosuppressive agents Immunotherapy Influence Interferon Interleukin 12 Interleukin 2 Isoflavones Kinases Lead compounds Ligands Lymphocytes Lymphocytes T Melanoma Melanoma, Experimental - drug therapy Melanoma, Experimental - immunology Mice, Inbred C57BL Neoplasm Transplantation Pharmacology Pharmacy Prostate Proteins Recurrence (Disease) Risk factors Skin cancer Spleen Studies T-Lymphocytes - drug effects T-Lymphocytes - immunology Toll-like receptors Toxicity Toxicology Triterpenes - pharmacology Tumor cells Tumors Viability γ-Interferon |
| title | Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin |
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