{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:54:23Z","timestamp":1790520863646,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T00:00:00Z","timestamp":1585612800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T00:00:00Z","timestamp":1585612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE025804"],"award-info":[{"award-number":["R01DE025804"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma associated with infection by Kaposi sarcoma-associated herpes virus (KSHV). PEL is an aggressive disease with extremely poor prognosis when treated with conventional chemotherapy. Narciclasine, a natural product present in <jats:italic>Amaryllidaceae<\/jats:italic> family of flowering plants including daffodils, belongs to a class of molecules termed \u2018isocarbostyril alkaloid\u2019. We have found that narciclasine displays preferential cytotoxicity towards PEL at low nanomolar concentrations and is approximately 10 and 100-fold more potent than its structural analogs lycoricidine and lycorine, respectively. Narciclasine arrested cell-cycle progression at the G<jats:sub>1<\/jats:sub> phase and induced apoptosis in PEL, which is accompanied by activation of caspase-3\/7, cleavage of PARP and increase in the surface expression of Annexin-V. Although narciclasine treatment resulted in a marked decrease in the expression of MYC and its direct target genes,time-course experiments revealed that MYC is not a direct target of narciclasine. Narciclasine treatment neither induces the expression of KSHV-RTA\/ORF50 nor the production of infectious KSHV virions in PEL. Finally, narciclasine provides dramatic survival advantages to mice in two distinct mouse xenograft models of PEL. In conclusion, our results suggest that narciclasine could be a promising agent for the treatment of PEL.<\/jats:p>","DOI":"10.1038\/s41598-020-62690-9","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T10:03:41Z","timestamp":1585649021000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-6886","authenticated-orcid":false,"given":"Ramakrishnan","family":"Gopalakrishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hittu","family":"Matta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunju","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preet M.","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,31]]},"reference":[{"key":"62690_CR1","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1056\/NEJM199505043321802","volume":"332","author":"E Cesarman","year":"1995","unstructured":"Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M. Kaposi\u2019s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 332, 1186\u20131191, https:\/\/doi.org\/10.1056\/NEJM199505043321802 (1995).","journal-title":"N. Engl. J. Med."},{"key":"62690_CR2","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1159\/000097460","volume":"117","author":"Y Kobayashi","year":"2007","unstructured":"Kobayashi, Y. et al. Comparison of human herpes virus 8 related primary effusion lymphoma with human herpes virus 8 unrelated primary effusion lymphoma-like lymphoma on the basis of HIV: report of 2 cases and review of 212 cases in the literature. Acta Haematol. 117, 132\u2013144, https:\/\/doi.org\/10.1159\/000097460 (2007).","journal-title":"Acta Haematol."},{"key":"62690_CR3","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1021\/jm8013585","volume":"52","author":"L Ingrassia","year":"2009","unstructured":"Ingrassia, L. et al. Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents. J. Med. Chem. 52, 1100\u20131114, https:\/\/doi.org\/10.1021\/jm8013585 (2009).","journal-title":"J. Med. Chem."},{"key":"62690_CR4","doi-asserted-by":"publisher","first-page":"4575","DOI":"10.1096\/fj.10-162263","volume":"24","author":"G Van Goietsenoven","year":"2010","unstructured":"Van Goietsenoven, G. et al. Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas. FASEB J. 24, 4575\u20134584, https:\/\/doi.org\/10.1096\/fj.10-162263 (2010).","journal-title":"FASEB J."},{"key":"62690_CR5","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1055\/s-0042-115034","volume":"82","author":"R Furst","year":"2016","unstructured":"Furst, R. Narciclasine - an Amaryllidaceae Alkaloid with Potent Antitumor and Anti-Inflammatory Properties. Planta Med. 82, 1389\u20131394, https:\/\/doi.org\/10.1055\/s-0042-115034 (2016).","journal-title":"Planta Med."},{"key":"62690_CR6","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1158\/1535-7163.MCT-08-0932","volume":"8","author":"F Lefranc","year":"2009","unstructured":"Lefranc, F. et al. Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. Mol. Cancer Ther. 8, 1739\u20131750, https:\/\/doi.org\/10.1158\/1535-7163.MCT-08-0932 (2009).","journal-title":"Mol. Cancer Ther."},{"key":"62690_CR7","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1038\/nrc2231","volume":"8","author":"N Meyer","year":"2008","unstructured":"Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976\u2013990, https:\/\/doi.org\/10.1038\/nrc2231 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"62690_CR8","doi-asserted-by":"publisher","first-page":"2928","DOI":"10.1038\/onc.2013.242","volume":"33","author":"B Tolani","year":"2014","unstructured":"Tolani, B., Gopalakrishnan, R., Punj, V., Matta, H. & Chaudhary, P. M. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene 33, 2928\u20132937, https:\/\/doi.org\/10.1038\/onc.2013.242 (2014).","journal-title":"Oncogene"},{"key":"62690_CR9","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1038\/onc.2015.245","volume":"35","author":"R Gopalakrishnan","year":"2016","unstructured":"Gopalakrishnan, R., Matta, H., Tolani, B., Triche, T. Jr. & Chaudhary, P. M. Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors. Oncogene 35, 1797\u20131810, https:\/\/doi.org\/10.1038\/onc.2015.245 (2016).","journal-title":"Oncogene"},{"key":"62690_CR10","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1158\/1535-7163.MCT-06-0782","volume":"6","author":"CR Evelyn","year":"2007","unstructured":"Evelyn, C. R. et al. CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol. Cancer Ther. 6, 2249\u20132260, https:\/\/doi.org\/10.1158\/1535-7163.MCT-06-0782 (2007).","journal-title":"Mol. Cancer Ther."},{"key":"62690_CR11","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.chembiol.2012.05.009","volume":"19","author":"X Shang","year":"2012","unstructured":"Shang, X. et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem. Biol. 19, 699\u2013710, https:\/\/doi.org\/10.1016\/j.chembiol.2012.05.009 (2012).","journal-title":"Chem. Biol."},{"key":"62690_CR12","doi-asserted-by":"publisher","first-page":"3475","DOI":"10.1091\/mbc.e04-03-0218","volume":"15","author":"TP Kole","year":"2004","unstructured":"Kole, T. P., Tseng, Y., Huang, L., Katz, J. L. & Wirtz, D. Rho kinase regulates the intracellular micromechanical response of adherent cells to rho activation. Mol. Biol. Cell 15, 3475\u20133484, https:\/\/doi.org\/10.1091\/mbc.e04-03-0218 (2004).","journal-title":"Mol. Biol. Cell"},{"key":"62690_CR13","doi-asserted-by":"publisher","first-page":"8945","DOI":"10.1128\/JVI.00244-10","volume":"84","author":"X Li","year":"2010","unstructured":"Li, X., Chen, S., Feng, J., Deng, H. & Sun, R. Myc is required for the maintenance of Kaposi\u2019s sarcoma-associated herpesvirus latency. J. Virol. 84, 8945\u20138948, https:\/\/doi.org\/10.1128\/JVI.00244-10 (2010).","journal-title":"J. Virol."},{"key":"62690_CR14","doi-asserted-by":"publisher","first-page":"e1067","DOI":"10.1371\/journal.pone.0001067","volume":"2","author":"J Zhao","year":"2007","unstructured":"Zhao, J. et al. K13 blocks KSHV lytic replication and deregulates vIL6 and hIL6 expression: a model of lytic replication induced clonal selection in viral oncogenesis. PLoS One 2, e1067, https:\/\/doi.org\/10.1371\/journal.pone.0001067 (2007).","journal-title":"PLoS One"},{"key":"62690_CR15","doi-asserted-by":"publisher","first-page":"13069","DOI":"10.1073\/pnas.1002985107","volume":"107","author":"KA Sarosiek","year":"2010","unstructured":"Sarosiek, K. A. et al. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc. Natl Acad. Sci. USA 107, 13069\u201313074, https:\/\/doi.org\/10.1073\/pnas.1002985107 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"62690_CR16","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1182\/blood-2018-03-791426","volume":"132","author":"K Shimada","year":"2018","unstructured":"Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879\u20131888, https:\/\/doi.org\/10.1182\/blood-2018-03-791426 (2018).","journal-title":"Blood"},{"key":"62690_CR17","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1097\/MCP.0000000000000384","volume":"23","author":"N Arora","year":"2017","unstructured":"Arora, N., Gupta, A. & Sadeghi, N. Primary effusion lymphoma: current concepts and management. Curr. Opin. Pulm. Med. 23, 365\u2013370, https:\/\/doi.org\/10.1097\/MCP.0000000000000384 (2017).","journal-title":"Curr. Opin. Pulm. Med."},{"key":"62690_CR18","doi-asserted-by":"publisher","first-page":"e12518","DOI":"10.1111\/cpr.12518","volume":"51","author":"C Cao","year":"2018","unstructured":"Cao, C. et al. Narciclasine induces autophagy-dependent apoptosis in triple-negative breast cancer cells by regulating the AMPK-ULK1 axis. Cell Prolif. 51, e12518, https:\/\/doi.org\/10.1111\/cpr.12518 (2018).","journal-title":"Cell Prolif."},{"key":"62690_CR19","doi-asserted-by":"publisher","first-page":"265","DOI":"10.2741\/2063","volume":"12","author":"J Nicholas","year":"2007","unstructured":"Nicholas, J. Human herpesvirus 8-encoded proteins with potential roles in virus-associated neoplasia. Front. Biosci. 12, 265\u2013281 (2007).","journal-title":"Front. Biosci."},{"key":"62690_CR20","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/978-981-10-7230-7_15","volume":"1045","author":"T Watanabe","year":"2018","unstructured":"Watanabe, T., Sugimoto, A., Hosokawa, K. & Fujimuro, M. Signal Transduction Pathways Associated with KSHV-Related Tumors. Adv. Exp. Med. Biol. 1045, 321\u2013355, https:\/\/doi.org\/10.1007\/978-981-10-7230-7_15 (2018).","journal-title":"Adv. Exp. Med. Biol."},{"key":"62690_CR21","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1111\/jcmm.12493","volume":"19","author":"S Fuchs","year":"2015","unstructured":"Fuchs, S. et al. Haemanthus coccineus extract and its main bioactive component narciclasine display profound anti-inflammatory activities in vitro and in vivo. J. Cell Mol. Med. 19, 1021\u20131032, https:\/\/doi.org\/10.1111\/jcmm.12493 (2015).","journal-title":"J. Cell Mol. Med."},{"key":"62690_CR22","doi-asserted-by":"publisher","first-page":"5738","DOI":"10.1038\/sj.onc.1202976","volume":"18","author":"PM Chaudhary","year":"1999","unstructured":"Chaudhary, P. M., Jasmin, A., Eby, M. T. & Hood, L. Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18, 5738\u20135746 (1999).","journal-title":"Oncogene"},{"key":"62690_CR23","doi-asserted-by":"publisher","first-page":"13745","DOI":"10.1074\/jbc.M110480200","volume":"277","author":"L Liu","year":"2002","unstructured":"Liu, L. et al. The Human Herpes Virus 8-encoded Viral FLICE Inhibitory Protein Physically Associates with and Persistently Activates the Ikappa B Kinase Complex. J. Biol. Chem. 277, 13745\u201313751 (2002).","journal-title":"J. Biol. Chem."},{"key":"62690_CR24","doi-asserted-by":"publisher","first-page":"9399","DOI":"10.1073\/pnas.0308016101","volume":"101","author":"H Matta","year":"2004","unstructured":"Matta, H. & Chaudhary, P. M. Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc. Natl Acad. Sci. USA 101, 9399\u20139404 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"62690_CR25","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1182\/blood.V96.7.2537","volume":"96","author":"SA Keller","year":"2000","unstructured":"Keller, S. A., Schattner, E. J. & Cesarman, E. Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96, 2537\u20132542 (2000).","journal-title":"Blood"},{"key":"62690_CR26","doi-asserted-by":"publisher","first-page":"15049","DOI":"10.1002\/anie.201709712","volume":"56","author":"EH Southgate","year":"2017","unstructured":"Southgate, E. H., Holycross, D. R. & Sarlah, D. Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene. Angew. Chem. Int. Ed. Engl. 56, 15049\u201315052, https:\/\/doi.org\/10.1002\/anie.201709712 (2017).","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"62690_CR27","doi-asserted-by":"publisher","unstructured":"Bingham, T. W. et al. Enantioselective Synthesis of Isocarbostyril Alkaloids and Analogs Using Catalytic Dearomative Functionalization of Benzene. J Am Chem Soc, https:\/\/doi.org\/10.1021\/jacs.8b12123 (2018).","DOI":"10.1021\/jacs.8b12123"},{"key":"62690_CR28","doi-asserted-by":"publisher","first-page":"5016","DOI":"10.1158\/1078-0432.CCR-12-3510","volume":"19","author":"R Gopalakrishnan","year":"2013","unstructured":"Gopalakrishnan, R., Matta, H. & Chaudhary, P. M. A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-kappaB. Clin. Cancer Res. 19, 5016\u20135026, https:\/\/doi.org\/10.1158\/1078-0432.CCR-12-3510 (2013).","journal-title":"Clin. Cancer Res."},{"key":"62690_CR29","doi-asserted-by":"publisher","first-page":"6345","DOI":"10.1128\/JVI.00028-14","volume":"88","author":"B Tolani","year":"2014","unstructured":"Tolani, B., Matta, H., Gopalakrishnan, R., Punj, V. & Chaudhary, P. M. NEMO is essential for Kaposi\u2019s sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process. J. Virol. 88, 6345\u20136354, https:\/\/doi.org\/10.1128\/JVI.00028-14 (2014).","journal-title":"J. Virol."},{"key":"62690_CR30","doi-asserted-by":"publisher","first-page":"27988","DOI":"10.1074\/jbc.M110.213363","volume":"286","author":"Y Yang","year":"2011","unstructured":"Yang, Y. et al. Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. J. Biol. Chem. 286, 27988\u201327997, https:\/\/doi.org\/10.1074\/jbc.M110.213363 (2011).","journal-title":"J. Biol. Chem."},{"key":"62690_CR31","doi-asserted-by":"publisher","first-page":"e36601","DOI":"10.1371\/journal.pone.0036601","volume":"7","author":"H Matta","year":"2012","unstructured":"Matta, H. et al. Kaposi\u2019s sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-kappaB pathway independent of TRAF6, TAK1 and LUBAC. PLoS One 7, e36601, https:\/\/doi.org\/10.1371\/journal.pone.0036601 (2012).","journal-title":"PLoS One"},{"key":"62690_CR32","doi-asserted-by":"publisher","first-page":"21555","DOI":"10.1074\/jbc.M111.224048","volume":"286","author":"H Matta","year":"2011","unstructured":"Matta, H. et al. A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-kappaB in a negative feedback manner. J. Biol. Chem. 286, 21555\u201321564, https:\/\/doi.org\/10.1074\/jbc.M111.224048 (2011).","journal-title":"J. Biol. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62690-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62690-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62690-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T08:51:33Z","timestamp":1670316693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-62690-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,31]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["62690"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-62690-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,31]]},"assertion":[{"value":"30 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5712"}}