{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T18:49:53Z","timestamp":1740163793313,"version":"3.37.3"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of\u2009&gt;\u200925,000 synthetic and natural product compounds as well as\u2009&gt;\u200920,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NF\u03baB inhibition while also suggesting the importance of zinc and\/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.<\/jats:p>","DOI":"10.1038\/s41598-021-93097-9","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T10:03:04Z","timestamp":1625047384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of natural product modulators of Merkel cell carcinoma cell growth and survival"],"prefix":"10.1038","volume":"11","author":[{"given":"Emily A.","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasha T.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara","family":"Gelb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid A.","family":"Garman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina I.","family":"Goncharova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi R.","family":"Bokesch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Kwon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen L.","family":"Wendt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Cichewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirk R.","family":"Gustafson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac","family":"Brownell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis J.","family":"Henrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"93097_CR1","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1002\/mc.23042","volume":"58","author":"L Cohen","year":"2019","unstructured":"Cohen, L. & Tsai, K. Y. Molecular and immune targets for Merkel cell carcinoma therapy and prevention. Mol. Carcinog. 58, 1602\u20131611 (2019).","journal-title":"Mol. Carcinog."},{"key":"93097_CR2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.currproblcancer.2010.01.001","volume":"34","author":"M Agelli","year":"2010","unstructured":"Agelli, M., Clegg, L. X., Becker, J. C. & Rollison, D. E. The etiology and epidemiology of Merkel cell carcinoma. Curr. Probl. Cancer. 34, 14\u201337 (2010).","journal-title":"Curr. Probl. Cancer."},{"key":"93097_CR3","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/s41571-018-0103-2","volume":"15","author":"PW Harms","year":"2018","unstructured":"Harms, P. W. et al. The biology and treatment of Merkel cell carcinoma: Current understanding and research priorities. Nat. Rev. Clin. Oncol. 15, 763\u2013776 (2018).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"93097_CR4","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1200\/JOP.2016.013367","volume":"12","author":"PD Banks","year":"2016","unstructured":"Banks, P. D., Sandhu, S., Gyorki, D. E., Johnston, M. L. & Rischin, D. Recent insights and advances in the management of Merkel cell carcinoma. J. Oncol. Pract. 12, 637\u2013646 (2016).","journal-title":"J. Oncol. Pract."},{"key":"93097_CR5","doi-asserted-by":"publisher","first-page":"4371","DOI":"10.1200\/JCO.2003.03.154","volume":"21","author":"M Poulsen","year":"2003","unstructured":"Poulsen, M. et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin\/etoposide and radiation: A Trans-Tasman Radiation Oncology Group Study\u2014TROG 96:07. J. Clin. Oncol. 21, 4371\u20134376 (2003).","journal-title":"J. Clin. Oncol."},{"key":"93097_CR6","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1007\/s40257-019-00427-9","volume":"20","author":"M Samimi","year":"2019","unstructured":"Samimi, M. Immune checkpoint inhibitors and beyond: an overview of immune-based therapies in Merkel cell carcinoma. Am. J. Clin. Dermatol. 20, 391\u2013407 (2019).","journal-title":"Am. J. Clin. Dermatol."},{"key":"93097_CR7","doi-asserted-by":"publisher","first-page":"e519","DOI":"10.14694\/EdBook_AM.2015.35.e519","volume":"2015","author":"R Tothill","year":"2015","unstructured":"Tothill, R., Estall, V. & Rischin, D. Merkel cell carcinoma: Emerging biology, current approaches, and future directions. Am. Soc. Clin. Oncol. Educ. Book. 2015, e519-526 (2015).","journal-title":"Am. Soc. Clin. Oncol. Educ. Book."},{"key":"93097_CR8","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/j.drudis.2008.07.004","volume":"13","author":"AL Harvey","year":"2008","unstructured":"Harvey, A. L. Natural products in drug discovery. Drug Discov. Today. 13, 894\u2013901 (2008).","journal-title":"Drug Discov. Today."},{"key":"93097_CR9","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","volume":"83","author":"DJ Newman","year":"2020","unstructured":"Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019. J. Nat. Prod. 83, 770\u2013803 (2020).","journal-title":"J. Nat. Prod."},{"key":"93097_CR10","doi-asserted-by":"publisher","first-page":"35","DOI":"10.3390\/biology9020035","volume":"9","author":"W Liu","year":"2020","unstructured":"Liu, W., Krump, N. A., Herlyn, M. & You, J. Combining DNA damage induction with BCL-2 inhibition to enhance Merkel cell carcinoma cytotoxicity. Biology 9, 35 (2020).","journal-title":"Biology"},{"key":"93097_CR11","doi-asserted-by":"publisher","first-page":"E803","DOI":"10.3390\/cells8080803","volume":"8","author":"JC Chamcheu","year":"2019","unstructured":"Chamcheu, J. C. et al. Role and therapeutic targeting of the PI3K\/Akt\/mTOR signaling pathway in skin cancer: A review of current status and future trends on natural and synthetic agents therapy. Cells 8, E803 (2019).","journal-title":"Cells"},{"key":"93097_CR12","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/ijc.2910600115","volume":"60","author":"JH Leonard","year":"1995","unstructured":"Leonard, J. H., Dash, P., Holland, P., Kearsley, J. H. & Bell, J. R. Characterisation of four Merkel cell carcinoma adherent cell lines. Int. J. Cancer. 60, 100\u2013107 (1995).","journal-title":"Int. J. Cancer."},{"key":"93097_CR13","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/0190-9622(93)70236-M","volume":"29","author":"SG Ronan","year":"1993","unstructured":"Ronan, S. G., Green, A. D., Shilkaitis, A., Huang, T. S. & Das Gupta, T. K. Merkel cell carcinoma: In vitro and in vivo characteristics of a new cell line. J. Am. Acad. Dermatol. 29, 715\u2013722 (1993).","journal-title":"J. Am. Acad. Dermatol."},{"key":"93097_CR14","first-page":"302","volume":"56","author":"ST Rosen","year":"1987","unstructured":"Rosen, S. T. et al. Establishment and characterization of a neuroendocrine skin carcinoma cell line. Lab Invest. 56, 302\u2013312 (1987).","journal-title":"Lab Invest."},{"key":"93097_CR15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/0169-6009(91)90088-H","volume":"14","author":"EM Martin","year":"1991","unstructured":"Martin, E. M. et al. Parathyroid hormone-related protein, chromogranin A, and calcitonin gene products in the neuroendocrine skin carcinoma cell lines MKL1 and MKL2. Bone Miner. 14, 113\u2013120 (1991).","journal-title":"Bone Miner."},{"key":"93097_CR16","doi-asserted-by":"publisher","first-page":"7064","DOI":"10.1128\/JVI.02400-09","volume":"84","author":"R Houben","year":"2010","unstructured":"Houben, R. et al. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J. Virol. 84, 7064\u20137072 (2010).","journal-title":"J. Virol."},{"key":"93097_CR17","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1083\/jcb.106.3.761","volume":"106","author":"P Boukamp","year":"1988","unstructured":"Boukamp, P. et al. Normal kerotinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106, 761\u2013771 (1988).","journal-title":"J. Cell Biol."},{"key":"93097_CR18","first-page":"4827","volume":"48","author":"DA Scudiero","year":"1988","unstructured":"Scudiero, D. A. et al. Evaluation of a soluble tetrazolium\/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 48, 4827\u20134833 (1988).","journal-title":"Cancer Res."},{"key":"93097_CR19","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.1038\/jid.2014.138","volume":"134","author":"ME Verhaegen","year":"2014","unstructured":"Verhaegen, M. E. et al. Merkel cell carcinoma dependence on bcl-2 family members for survival. J. Invest. Dermatol. 134, 2241\u20132250 (2014).","journal-title":"J. Invest. Dermatol."},{"key":"93097_CR20","doi-asserted-by":"publisher","first-page":"13356","DOI":"10.1126\/scitranslmed.3003713","volume":"4","author":"R Arora","year":"2012","unstructured":"Arora, R. et al. Survivin is a therapeutic target in Merkel cell carcinoma. Sci. Transl. Med. 4, 13356 (2012).","journal-title":"Sci. Transl. Med."},{"key":"93097_CR21","doi-asserted-by":"publisher","first-page":"E57099","DOI":"10.1371\/journal.pone.0057099","volume":"8","author":"SD Mertins","year":"2013","unstructured":"Mertins, S. D. et al. A small molecule (pluripotin) as a tool for studying cancer stem cell biology: Proof of concept. PLoS ONE 8, E57099 (2013).","journal-title":"PLoS ONE"},{"key":"93097_CR22","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.stem.2013.08.002","volume":"13","author":"W Li","year":"2013","unstructured":"Li, W., Li, K., Wei, W. & Ding, S. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 13, 270\u2013283 (2013).","journal-title":"Cell Stem Cell"},{"key":"93097_CR23","doi-asserted-by":"publisher","first-page":"275","DOI":"10.4172\/jpb.1000291","volume":"6","author":"Q Shao","year":"2013","unstructured":"Shao, Q. et al. A proteomic study of human Merkel cell carcinoma. J. Proteom. Bioinform. 6, 275\u2013282 (2013).","journal-title":"J. Proteom. Bioinform."},{"key":"93097_CR24","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1177\/108705719900400206","volume":"4","author":"JH Zhang","year":"1999","unstructured":"Zhang, J. H., Chung, T. D. & Oldenburg, K. R. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen. 4, 67\u201373 (1999).","journal-title":"J. Biomol. Screen."},{"key":"93097_CR25","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1007\/s00262-019-02341-9","volume":"68","author":"S Ugurel","year":"2019","unstructured":"Ugurel, S. et al. MHC class-I downregulation in PD-1\/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: A case series. Cancer Immunol. Immunother. 68, 983\u2013990 (2019).","journal-title":"Cancer Immunol. Immunother."},{"key":"93097_CR26","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1038\/s41598-017-02608-0","volume":"7","author":"C Ritter","year":"2017","unstructured":"Ritter, C. et al. Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma. Sci. Rep. 7, 2290 (2017).","journal-title":"Sci. Rep."},{"key":"93097_CR27","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.bcp.2014.12.008","volume":"93","author":"BB Hasinoff","year":"2015","unstructured":"Hasinoff, B. B. et al. Cellular mechanisms of the cytotoxicity of the anticancer drug elesclomol and its complex with Cu(II). Biochem. Pharmacol. 93, 266\u2013276 (2015).","journal-title":"Biochem. Pharmacol."},{"key":"93097_CR28","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/(SICI)1098-2744(199808)22:4<235::AID-MC5>3.0.CO;2-I","volume":"22","author":"GY Liu","year":"1998","unstructured":"Liu, G. Y., Frank, N., Bartsch, H. & Lin, J. K. Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos\/c-jun, and p53 proteins. Mol. Carcinog. 22, 235\u2013246 (1998).","journal-title":"Mol. Carcinog."},{"key":"93097_CR29","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1084\/jem.175.5.1181","volume":"175","author":"R Schreck","year":"1992","unstructured":"Schreck, R., Meier, B., M\u00e4nnel, D. N., Dr\u00f6ge, W. & Baeuerle, P. A. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175, 1181\u20131194 (1992).","journal-title":"J. Exp. Med."},{"key":"93097_CR30","doi-asserted-by":"publisher","first-page":"3248","DOI":"10.2174\/1381612825666190816233755","volume":"25","author":"Q Yang","year":"2019","unstructured":"Yang, Q. et al. An updated review of Disulfiram: Molecular targets and strategies for cancer treatment. Curr. Pharm. Des. 25, 3248\u20133256 (2019).","journal-title":"Curr. Pharm. Des."},{"key":"93097_CR31","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1002\/(SICI)1097-4547(20000101)59:1<117::AID-JNR14>3.0.CO;2-Q","volume":"59","author":"KC Chung","year":"2000","unstructured":"Chung, K. C. et al. Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases. J. Neurosci Res. 59, 117\u2013125 (2000).","journal-title":"J. Neurosci Res."},{"key":"93097_CR32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.bcp.2017.07.011","volume":"143","author":"EH Lee","year":"2017","unstructured":"Lee, E. H., Kim, S. S. & Seo, S. R. Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction. Biochem. Pharmacol. 143, 107\u2013117 (2017).","journal-title":"Biochem. Pharmacol."},{"key":"93097_CR33","doi-asserted-by":"publisher","first-page":"13853","DOI":"10.1128\/JVI.02159-13","volume":"87","author":"DA Griffiths","year":"2013","unstructured":"Griffiths, D. A. et al. Merkel cell polyomavirus small T antigen targets the NEMO adaptor protein to disrupt inflammatory signaling. J. Virol. 87, 13853\u201313867 (2013).","journal-title":"J. Virol."},{"key":"93097_CR34","doi-asserted-by":"publisher","first-page":"e1006020","DOI":"10.1371\/journal.ppat.1006020","volume":"12","author":"C Berrios","year":"2016","unstructured":"Berrios, C. et al. Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation. PLoS Pathog. 12, e1006020 (2016).","journal-title":"PLoS Pathog."},{"key":"93097_CR35","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1158\/1541-7786.MCR-20-0587","volume":"18","author":"J Zhao","year":"2020","unstructured":"Zhao, J. et al. Merkel cell polyomavirus small T antigen activates noncanonical NF\u03baB signaling to promote tumorigenesis. Mol. Cancer Res. 18, 1623\u20131637 (2020).","journal-title":"Mol. Cancer Res."},{"key":"93097_CR36","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1002\/cne.10804","volume":"464","author":"T Vitalis","year":"2003","unstructured":"Vitalis, T. et al. Developmental expression pattern of monoamine oxidases in sensory organs and neural crest derivatives. J. Comp. Neurol. 464, 392\u2013403 (2003).","journal-title":"J. Comp. Neurol."},{"key":"93097_CR37","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.yexcr.2004.04.017","volume":"298","author":"I Kim","year":"2004","unstructured":"Kim, I. et al. Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis. Exp. Cell Res. 298, 229\u2013238 (2004).","journal-title":"Exp. Cell Res."},{"key":"93097_CR38","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.2174\/1871520615666160504095040","volume":"16","author":"Y Jiao","year":"2016","unstructured":"Jiao, Y., Hannafon, B. N. & Ding, W. Q. Disulfiram\u2019s anticancer activity: Evidence and mechanisms. Anticancer Agents Med. Chem. 16, 1378\u20131384 (2016).","journal-title":"Anticancer Agents Med. Chem."},{"key":"93097_CR39","doi-asserted-by":"publisher","first-page":"240","DOI":"10.3390\/cancers10070240","volume":"10","author":"N Tsesmetzis","year":"2018","unstructured":"Tsesmetzis, N., Paulin, C. B., Rudd, S. G. & Herold, N. Nucleobase and nucleoside analogues: Resistance and re-sensitisation at the level of pharmacokinetics, pharmacodynamics and metabolism. Cancers (Basel) 10, 240 (2018).","journal-title":"Cancers (Basel)"},{"key":"93097_CR40","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/jnci\/51.1.139","volume":"51","author":"GJ Van Giessen","year":"1973","unstructured":"Van Giessen, G. J., Crim, J. A., Petering, D. H. & Petering, H. G. Effect of heavy metals on the in vitro cytotoxicity of 3-Ethoxy-2-Oxobutyraldehyde bis(thiosemicarbazone) and related compounds. J. Natl. Cancer Inst. 51, 139\u2013146 (1973).","journal-title":"J. Natl. Cancer Inst."},{"key":"93097_CR41","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1124\/jpet.105.096891","volume":"317","author":"A Martirosyan","year":"2006","unstructured":"Martirosyan, A. et al. Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells. J. Pharmacol. Exp. Ther. 317, 546\u2013552 (2006).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"93097_CR42","doi-asserted-by":"publisher","first-page":"173580","DOI":"10.1016\/j.ejphar.2020.173580","volume":"887","author":"J Benjanuwattra","year":"2020","unstructured":"Benjanuwattra, J., Chaiyawat, P., Pruksakorn, D. & Koonrungsesomboon, N. Therapeutic potential and molecular mechanisms of mycophenolic acid as an anticancer agent. Euro. J. Pharmacol. 887, 173580 (2020).","journal-title":"Euro. J. Pharmacol."},{"key":"93097_CR43","doi-asserted-by":"publisher","first-page":"102417","DOI":"10.1016\/j.bioorg.2019.103417","volume":"94","author":"L Yuan","year":"2020","unstructured":"Yuan, L. et al. A novel cathepsin L inhibitor prevents the progression of idiopathic pulmonary fibrosis. Bioorg. Chem. 94, 102417 (2020).","journal-title":"Bioorg. Chem."},{"key":"93097_CR44","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1021\/np049595s","volume":"68","author":"AR Carroll","year":"2005","unstructured":"Carroll, A. R., Ngo, A., Quinn, R. J., Redburn, J. & Hooper, J. N. A. Petrosamine B, an inhibitor of the Heliobacter pylori enzyme aspartyl semialdehyde dehydrogenase from the Australian sponge Oceanapia sp. J. Nat. Prod. 68, 804\u2013806 (2005).","journal-title":"J. Nat. Prod."},{"key":"93097_CR45","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.4155\/fmc-2017-0294","volume":"10","author":"TT Ho","year":"2018","unstructured":"Ho, T. T., Tran, Q. T. & Chai, C. L. The polypharmacology of natural products. Future Med. Chem. 10, 1361\u20131368 (2018).","journal-title":"Future Med. Chem."},{"key":"93097_CR46","doi-asserted-by":"publisher","first-page":"E731","DOI":"10.3390\/nu10060731","volume":"10","author":"AK Singh","year":"2018","unstructured":"Singh, A. K., Bishayee, A. & Pandey, A. K. Targeting histone deacetylases with natural and synthetic agents: An emerging anticancer strategy. Nutrients 10, E731 (2018).","journal-title":"Nutrients"},{"key":"93097_CR47","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.fct.2019.01.018","volume":"125","author":"SK Tripathi","year":"2019","unstructured":"Tripathi, S. K., Panda, M. & Biswal, B. K. Emerging role of plumbagin: Cytotoxic potential and pharmaceutical relevance towards cancer therapy. Food Chem. Toxicol. 125, 566\u2013582 (2019).","journal-title":"Food Chem. Toxicol."},{"doi-asserted-by":"crossref","unstructured":"Binoy, A. et al. Plumbagin induces paraptosis in cancer cells by disrupting the sulfhydryl homeostasis and proteasomal function. Chem. Biol. Interact. 310, 108733 (2019) (corrigendum, 311, 108791, 2019).","key":"93097_CR48","DOI":"10.1016\/j.cbi.2019.108791"},{"key":"93097_CR49","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.ejmech.2018.04.001","volume":"151","author":"RK Singh","year":"2018","unstructured":"Singh, R. K., Kumar, S., Prasad, D. N. & Bhardwaj, T. R. Therapeutic journey of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. Eur. J. Med. Chem. 151, 401\u2013433 (2018).","journal-title":"Eur. J. Med. Chem."},{"key":"93097_CR50","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.2174\/0929867324666170124145557","volume":"24","author":"J Blasiak","year":"2017","unstructured":"Blasiak, J. DNA-damaging anticancer drugs: A perspective for DNA repair-oriented therapy. Curr. Med. Chem. 24, 1488\u20131503 (2017).","journal-title":"Curr. Med. Chem."},{"key":"93097_CR51","doi-asserted-by":"publisher","first-page":"363","DOI":"10.2174\/1568011054222364","volume":"5","author":"EL Baldwin","year":"2005","unstructured":"Baldwin, E. L. & Osheroff, N. Etoposide, topoisomerase II and cancer. Curr. Med. Chem. Anticancer Agents. 5, 363\u2013372 (2005).","journal-title":"Curr. Med. Chem. Anticancer Agents."},{"key":"93097_CR52","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/217250a0","volume":"217","author":"BA Booth","year":"1968","unstructured":"Booth, B. A., Johns, D. G., Bertino, J. R. & Sartorelli, A. C. Sites of inhibition of DNA synthesis by kethoxal bis(thiosemicarbazone). Nature 217, 250\u2013251 (1968).","journal-title":"Nature"},{"key":"93097_CR53","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1080\/10428194.2019.1672060","volume":"61","author":"M Molica","year":"2020","unstructured":"Molica, M. et al. The role of cladribine in acute myeloid leukemia: An old drug up to new tricks. Leuk. Lymphoma. 61, 536\u2013545 (2020).","journal-title":"Leuk. Lymphoma."},{"key":"93097_CR54","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/978-981-10-3332-2_16","volume-title":"Chemotherapy for Leukemia: Novel Drugs and Treatments","author":"WB Parker","year":"2017","unstructured":"Parker, W. B. & Gandhi, V. Clofarabine: Structure, mechanism of action, and clinical pharmacology. In Chemotherapy for Leukemia: Novel Drugs and Treatments (ed. Ueda, T.) 261\u2013286 (Springer, 2017)."},{"key":"93097_CR55","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.canlet.2004.04.023","volume":"220","author":"N Fukamiya","year":"2005","unstructured":"Fukamiya, N. et al. Structure-activity relationships of quassinoids for eukaryotic protein synthesis. Cancer Lett. 220, 37\u201348 (2005).","journal-title":"Cancer Lett."},{"key":"93097_CR56","doi-asserted-by":"publisher","first-page":"5365","DOI":"10.1074\/jbc.REV118.002956","volume":"294","author":"CS Francklyn","year":"2019","unstructured":"Francklyn, C. S. & Mullen, P. Progress and challenges in aminoacyl tRNA synthesis-based therapeutics. J. Biol. Chem. 294, 5365\u20135385 (2019).","journal-title":"J. Biol. Chem."},{"key":"93097_CR57","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1016\/0006-2952(74)90255-X","volume":"23","author":"AG Bolt","year":"1974","unstructured":"Bolt, A. G. & Sleigh, M. J. Furoxanobenzofuroxan, a selective monoamine oxidase inhibitor. Biochem Pharmacol. 23, 1969\u20131977 (1974).","journal-title":"Biochem Pharmacol."},{"key":"93097_CR58","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1021\/acs.jmedchem.9b01509","volume":"63","author":"L Peterkova","year":"2020","unstructured":"Peterkova, L., Kmon\u00edckova, E., Ruml, T. & Rimpelova, S. Sarco\/Endoplasmic reticulum calcium ATPase inhibitors: Beyond anticancer perspective. J. Med. Chem. 63, 1937\u20131963 (2020).","journal-title":"J. Med. Chem."},{"key":"93097_CR59","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1021\/acs.jnatprod.6b01167","volume":"80","author":"Z Wu","year":"2017","unstructured":"Wu, Z. et al. Englerins: A Comprehensive review. J. Nat. Prod. 80, 771\u2013781 (2017).","journal-title":"J. Nat. Prod."},{"doi-asserted-by":"crossref","unstructured":"Du, L. et al. Crowdsourcing natural products discovery to access uncharted dimensions of fungal metabolite diversity. Angew Chem. Int. Ed. Engl. 53, 804\u2013809 (2014) (erratum, 54, 6671, 2015).","key":"93097_CR60","DOI":"10.1002\/anie.201306549"},{"key":"93097_CR61","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/bs.adgen.2020.11.006","volume":"107","author":"K Bhattarai","year":"2021","unstructured":"Bhattarai, K. et al. Fungal natural products galaxy: Biochemistry and molecular genetics toward blockbuster drugs discovery. Adv. Genet. 107, 193\u2013284 (2021).","journal-title":"Adv. Genet."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93097-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93097-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93097-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T10:25:23Z","timestamp":1670063123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93097-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["93097"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-93097-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,6,30]]},"assertion":[{"value":"11 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2021","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":"13597"}}