Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway
Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors...
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| Veröffentlicht in: | Biomolecules (Basel, Switzerland) Switzerland), 2020-11, Vol.10 (11), p.1521, Article 1521 |
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| creator | Lee, Ji Hae Park, So-Young Hwang, Wonbin Sung, Jee Young Cho, Myoung-Lae Shim, Jaegal Kim, Yong-Nyun Yoon, Kyungsil |
| description | Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment. |
| doi_str_mv | 10.3390/biom10111521 |
| format | Article |
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Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment.</description><identifier>ISSN: 2218-273X</identifier><identifier>EISSN: 2218-273X</identifier><identifier>DOI: 10.3390/biom10111521</identifier><identifier>PMID: 33172112</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject>A549 Cells ; Alkaloids ; Animals ; apoptosis ; Apoptosis - drug effects ; Biochemistry & Molecular Biology ; Caenorhabditis elegans - drug effects ; Caenorhabditis elegans - metabolism ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cephalotaxus - chemistry ; Harringtonines - pharmacology ; Health aspects ; Humans ; isoharringtonine ; Life Sciences & Biomedicine ; Lung cancer, Non-small cell ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mice ; NR4A1 ; NSCLC ; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics ; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism ; Physiological aspects ; Science & Technology ; Signal Transduction - drug effects ; tumorspheroids ; Xenograft Model Antitumor Assays</subject><ispartof>Biomolecules (Basel, Switzerland), 2020-11, Vol.10 (11), p.1521, Article 1521</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>6</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000593033900001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c478t-bea48fe5684fff952f890ec2884d24b137cb018e806898619e1e5c08fd97d3103</citedby><cites>FETCH-LOGICAL-c478t-bea48fe5684fff952f890ec2884d24b137cb018e806898619e1e5c08fd97d3103</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/PMC7694770/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694770/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33172112$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Ji Hae</creatorcontrib><creatorcontrib>Park, So-Young</creatorcontrib><creatorcontrib>Hwang, Wonbin</creatorcontrib><creatorcontrib>Sung, Jee Young</creatorcontrib><creatorcontrib>Cho, Myoung-Lae</creatorcontrib><creatorcontrib>Shim, Jaegal</creatorcontrib><creatorcontrib>Kim, Yong-Nyun</creatorcontrib><creatorcontrib>Yoon, Kyungsil</creatorcontrib><title>Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway</title><title>Biomolecules (Basel, Switzerland)</title><addtitle>BIOMOLECULES</addtitle><addtitle>Biomolecules</addtitle><description>Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment.</description><subject>A549 Cells</subject><subject>Alkaloids</subject><subject>Animals</subject><subject>apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry & Molecular Biology</subject><subject>Caenorhabditis elegans - drug effects</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cephalotaxus - chemistry</subject><subject>Harringtonines - pharmacology</subject><subject>Health aspects</subject><subject>Humans</subject><subject>isoharringtonine</subject><subject>Life Sciences & Biomedicine</subject><subject>Lung cancer, Non-small cell</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>NR4A1</subject><subject>NSCLC</subject><subject>Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics</subject><subject>Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism</subject><subject>Physiological aspects</subject><subject>Science & Technology</subject><subject>Signal Transduction - drug effects</subject><subject>tumorspheroids</subject><subject>Xenograft Model Antitumor Assays</subject><issn>2218-273X</issn><issn>2218-273X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1rFDEUwAdRbKm9eZaAF0FX8zUzyUVYBj8WFhWs4C1kMi-7KTvJmmRa-t-b6dZlezOEJLz8-PFe8qrqJcHvGZP4Q-_CSDAhpKbkSXVOKREL2rLfT0_OZ9VlSte4DFEmZc-rM8ZISwmh51VcpbDVMTq_ycE7D2jlh8lAQst92OeQXELBom_BL36OerdDHZRlPfkN6rQ3EO8DCTmPrqYxxLTfQgxuSOjGaZS3sy8Xe3IG_dB5e6vvXlTPrN4luHzYL6pfnz9ddV8X6-9fVt1yvTC8FXnRg-bCQt0Ibq2VNbVCYjBUCD5Q3hPWmh4TAQI3QoqGSCBQGyzsINuBEcwuqtXBOwR9rfbRjTreqaCdug-EuFE6Zmd2oBpWc8vBAG4wr7GQA5emHhgGqnUvm-L6eHDtp36EwUApSu8eSR_feLdVm3Cj2kbytp2TefMgiOHPBCmr0SVTnk57CFNSlNeyoZyxtqCvD-hGl9Sct6EYzYyrZcMbwmqK54zeHSgTQ0oR7DEZgtXcG-q0Nwr-6rSAI_yvEwrw9gDcQh9sMg7K7x6x0jy1ZHj2ljHrxP_Tncs6u-C7MPnM_gKp-tWn</recordid><startdate>20201106</startdate><enddate>20201106</enddate><creator>Lee, Ji Hae</creator><creator>Park, So-Young</creator><creator>Hwang, Wonbin</creator><creator>Sung, Jee Young</creator><creator>Cho, Myoung-Lae</creator><creator>Shim, Jaegal</creator><creator>Kim, Yong-Nyun</creator><creator>Yoon, Kyungsil</creator><general>Mdpi</general><general>MDPI AG</general><general>MDPI</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20201106</creationdate><title>Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway</title><author>Lee, Ji Hae ; Park, So-Young ; Hwang, Wonbin ; Sung, Jee Young ; Cho, Myoung-Lae ; Shim, Jaegal ; Kim, Yong-Nyun ; Yoon, Kyungsil</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-bea48fe5684fff952f890ec2884d24b137cb018e806898619e1e5c08fd97d3103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>A549 Cells</topic><topic>Alkaloids</topic><topic>Animals</topic><topic>apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biochemistry & Molecular Biology</topic><topic>Caenorhabditis elegans - drug effects</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cephalotaxus - chemistry</topic><topic>Harringtonines - pharmacology</topic><topic>Health aspects</topic><topic>Humans</topic><topic>isoharringtonine</topic><topic>Life Sciences & Biomedicine</topic><topic>Lung cancer, Non-small cell</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>NR4A1</topic><topic>NSCLC</topic><topic>Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics</topic><topic>Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism</topic><topic>Physiological aspects</topic><topic>Science & Technology</topic><topic>Signal Transduction - drug effects</topic><topic>tumorspheroids</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Ji Hae</creatorcontrib><creatorcontrib>Park, So-Young</creatorcontrib><creatorcontrib>Hwang, Wonbin</creatorcontrib><creatorcontrib>Sung, Jee Young</creatorcontrib><creatorcontrib>Cho, Myoung-Lae</creatorcontrib><creatorcontrib>Shim, Jaegal</creatorcontrib><creatorcontrib>Kim, Yong-Nyun</creatorcontrib><creatorcontrib>Yoon, Kyungsil</creatorcontrib><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Biomolecules (Basel, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Ji Hae</au><au>Park, So-Young</au><au>Hwang, Wonbin</au><au>Sung, Jee Young</au><au>Cho, Myoung-Lae</au><au>Shim, Jaegal</au><au>Kim, Yong-Nyun</au><au>Yoon, Kyungsil</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway</atitle><jtitle>Biomolecules (Basel, Switzerland)</jtitle><stitle>BIOMOLECULES</stitle><addtitle>Biomolecules</addtitle><date>2020-11-06</date><risdate>2020</risdate><volume>10</volume><issue>11</issue><spage>1521</spage><pages>1521-</pages><artnum>1521</artnum><issn>2218-273X</issn><eissn>2218-273X</eissn><abstract>Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment.</abstract><cop>BASEL</cop><pub>Mdpi</pub><pmid>33172112</pmid><doi>10.3390/biom10111521</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | A549 Cells Alkaloids Animals apoptosis Apoptosis - drug effects Biochemistry & Molecular Biology Caenorhabditis elegans - drug effects Caenorhabditis elegans - metabolism Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Cell Proliferation - drug effects Cephalotaxus - chemistry Harringtonines - pharmacology Health aspects Humans isoharringtonine Life Sciences & Biomedicine Lung cancer, Non-small cell Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice NR4A1 NSCLC Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism Physiological aspects Science & Technology Signal Transduction - drug effects tumorspheroids Xenograft Model Antitumor Assays |
| title | Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway |
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