{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:52:52Z","timestamp":1791553972027,"version":"4.3.4"},"reference-count":73,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005601","name":"CLL Global Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008882","name":"Texas State University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008882","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Targeting protein translation is a promising strategy in oncology, especially for malignancies dependent on short-lived survival factors. The clinical translation inhibitor homoharringtonine (HHT) was recently discontinued in the U.S. due to poor solubility and cardiotoxicity, creating an urgent need for new leads. We investigated structurally distinct Amaryllidaceae alkaloids, narciclasine (NCS), lycorine (LYC), and haemanthamine (HAEM), in models of chronic lymphocytic leukemia (CLL) and Richter transformation (RT). Using an optimized 10 L Soxhlet extraction of \u2019Carlton\u2019 daffodil bulbs, an unprecedented NCS yield of 250 mg\/kg was achieved, doubling previous laboratory records. NCS showed potent activity against primary CLL cells and the RT-derived HPRT1 line (IC50 = 50 nM), while normal T-cell viability remained largely unaffected at doses producing near-complete CLL cell depletion, indicating a favorable therapeutic window. O-Propargyl-puromycin incorporation and [3H]-leucine assays confirmed dose-dependent inhibition of de novo protein synthesis, triggering selective depletion of the short-lived anti-apoptotic protein Mcl-1 while leaving stable Bcl-2 unaffected. Mcl-1 loss induced mitochondrial depolarization, Annexin V\/PI positivity, and PARP cleavage. Combination studies with the Bcl-2 inhibitor venetoclax revealed synergistic activity across all compounds, most pronounced for HAEM, consistent with its comparatively modest Mcl-1 depletion. These findings establish that Amaryllidaceae alkaloids exploit the \u2033translational addiction\u2033 of leukemia cells to Mcl-1 and validate the isocarbostyril and phenanthridine scaffolds as mechanistically characterized leads. SAR-guided analogue optimization to improve pharmacokinetic properties while preserving the translational inhibition pharmacophore represents the planned next stage of this program.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00139","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:01:31Z","timestamp":1789117291000},"page":"2758-2771","source":"Crossref","is-referenced-by-count":0,"title":["From Daffodils\nto Drug Leads: Amaryllidaceae Alkaloids\nTarget Protein Translation in Chronic Lymphocytic Leukemia to Induce\nSelective Apoptosis"],"prefix":"10.1021","volume":"9","author":[{"given":"Rong","family":"Chen","sequence":"first","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77054"]},{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Rutledge","sequence":"additional","affiliation":[{"name":"Texas State University , , , ,","place":["San Marcos, Texas, United States, 78666"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson W.","family":"King","sequence":"additional","affiliation":[{"name":"Texas State University , , , ,","place":["San Marcos, Texas, United States, 78666"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Chen","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77054"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Xiong","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77054"]},{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Wierda","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puppala","family":"Sathish","sequence":"additional","affiliation":[{"name":"Texas State University , , , ,","place":["San Marcos, Texas, United States, 78666"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-1656","authenticated-orcid":true,"given":"Antonio","family":"Evidente","sequence":"additional","affiliation":[{"name":"National Research Council , , ,","place":["Pozzuoli, Italy, 80078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Anderson","sequence":"additional","affiliation":[{"name":"Texas State University , , , ,","place":["San Marcos, Texas, United States, 78666"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Plunkett","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77054"]},{"name":"The University of Texas MD Anderson Cancer Center , , , ,","place":["Houston, Texas, United States, 77030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-7367","authenticated-orcid":true,"given":"Alexander","family":"Kornienko","sequence":"additional","affiliation":[{"name":"Texas State University , , , ,","place":["San Marcos, Texas, United States, 78666"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"issue":"1","key":"2026100909103699700_cit1","doi-asserted-by":"publisher","DOI":"10.29333\/ejgm\/14040","article-title":"Antitumor evaluation of amaryllidaceae\nalkaloids on cancer cell lines: A literature review","volume":"21","author":"De Paiva","year":"2024","journal-title":"Electronic Journal of General Medicine"},{"issue":"13","key":"2026100909103699700_cit2","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.3390\/plants14131935","article-title":"The Occurrence and\nBioactivities of Amaryllidaceae Alkaloids from Plants: A Taxonomy-Guided\nGenera-Wide Review","volume":"14","author":"Lin","year":"2025","journal-title":"Plants"},{"issue":"10","key":"2026100909103699700_cit3","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.3390\/biomedicines11102619","article-title":"Benzoindolizidine Alkaloids Tylophorine and Lycorine\nand Their Analogues with Antiviral, Anti-Inflammatory, and Anticancer\nProperties: Promises and Challenges","volume":"11","author":"Di Sotto","year":"2023","journal-title":"Biomedicines"},{"issue":"1","key":"2026100909103699700_cit4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/jxb\/erae187","article-title":"Navigating Amaryllidaceae\nalkaloids: bridging gaps and charting biosynthetic territories","volume":"76","author":"Liyanage","year":"2025","journal-title":"Journal of Experimental Botany"},{"key":"2026100909103699700_cit5","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.biopha.2018.07.147","article-title":"Lycorine: A prospective\nnatural lead for anticancer drug discovery","volume":"107","author":"Roy","year":"2018","journal-title":"Biomedicine & Pharmacotherapy"},{"issue":"6","key":"2026100909103699700_cit6","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1021\/cr078198u","article-title":"Chemistry, Biology,\nand Medicinal Potential of Narciclasine\nand its Congeners","volume":"108","author":"Kornienko","year":"2008","journal-title":"Chem. Rev."},{"key":"2026100909103699700_cit7","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107449","article-title":"Harnessing\nnatural inhibitors of protein synthesis\nfor cancer therapy: A comprehensive review","volume":"209","author":"Liu","year":"2024","journal-title":"Pharmacological Research"},{"issue":"5","key":"2026100909103699700_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2022.103746","article-title":"Semisynthetic derivatives of haemanthamine\nand their in vitro antiproliferative activity evaluation against a\npanel of human cell lines","volume":"15","author":"Uher","year":"2022","journal-title":"Arabian Journal of\nChemistry"},{"issue":"3","key":"2026100909103699700_cit9","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.str.2018.01.009","article-title":"The Amaryllidaceae\nalkaloid haemanthamine binds the eukaryotic ribosome to repress cancer\ncell growth","volume":"26","author":"Pellegrino","year":"2018","journal-title":"Structure"},{"issue":"2","key":"2026100909103699700_cit10","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/0014-5793(75)80813-1","article-title":"Narciclasine:\nan antitumour alkaloid\nwhich blocks peptide bond formation by eukaryotic ribosomes","volume":"52","author":"Carrasco","year":"1975","journal-title":"FEBS Letters"},{"issue":"3","key":"2026100909103699700_cit11","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/0005-2787(76)90261-6","article-title":"Inhibitors\nof protein\nsynthesis in eukaryotic cells","volume":"425","author":"Jimenez","year":"1976","journal-title":"Biochimica Et\nBiophysica Acta (BBA) - Nucleic Acids and Protein Synthesis"},{"issue":"1\u20132","key":"2026100909103699700_cit12","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/0014-5793(75)80955-0","article-title":"Location of resistance to the alkaloid\nnarciclasine in the 60S ribosomal subunit","volume":"55","author":"Jimenez","year":"1975","journal-title":"FEBS\nLetters"},{"issue":"1","key":"2026100909103699700_cit13","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/0014-5793(75)80420-0","article-title":"Yeast ribosomal sensitivity\nand resistance\nto the Amaryllidaceae alkaloids","volume":"60","author":"Jimenez","year":"1975","journal-title":"FEBS Letters"},{"issue":"11","key":"2026100909103699700_cit14","doi-asserted-by":"publisher","first-page":"4575","DOI":"10.1096\/fj.10-162263","article-title":"Targeting of eEF1A with Amaryllidaceae isocarbostyrils\nas a strategy to combat melanomas","volume":"24","author":"Van Goietsenoven","year":"2010","journal-title":"FASEB J."},{"key":"2026100909103699700_cit15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76465","article-title":"Proteostasis is differentially\nmodulated by inhibition of translation initiation or elongation","volume":"12","author":"Clay","year":"2023","journal-title":"eLife"},{"issue":"2","key":"2026100909103699700_cit16","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/S0021-9258(17)36118-5","article-title":"Lycorine:\na eukaryotic termination inhibitor?","volume":"261","author":"Vrijsen","year":"1986","journal-title":"J. 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leukemia","volume":"383","author":"Burger","year":"2020","journal-title":"New England\nJournal of Medicine"},{"issue":"25","key":"2026100909103699700_cit26","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines\nfor diagnosis, indications for treatment, response assessment, and\nsupportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"2026100909103699700_cit27","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1522273","article-title":"Homoharringtonine: mechanisms, clinical applications and research\nprogress","volume":"15","author":"Wang","year":"2025","journal-title":"Frontiers in Oncology"},{"issue":"1","key":"2026100909103699700_cit28","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1182\/blood-2010-01-262808","article-title":"Homoharringtonine\nreduced Mcl-1 expression and induced apoptosis in chronic lymphocytic\nleukemia","volume":"117","author":"Chen","year":"2011","journal-title":"Blood"},{"issue":"01","key":"2026100909103699700_cit29","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1055\/s-2006-958007","article-title":"Cytotoxic activity\nof amaryllidaceae alkaloids","volume":"61","author":"Weniger","year":"1995","journal-title":"Planta Medica"},{"issue":"5076","key":"2026100909103699700_cit30","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/213595a0","article-title":"Narciclasine:\nan Antimitotic Substance from Narcissus Bulbs","volume":"213","author":"Ceriotti","year":"1967","journal-title":"Nature"},{"issue":"9","key":"2026100909103699700_cit31","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/S0031-9422(00)85963-4","article-title":"Occurrence\nof non-basic metabolites in Amaryllidaceae","volume":"8","author":"Piozzi","year":"1969","journal-title":"Phytochemistry"},{"issue":"9","key":"2026100909103699700_cit32","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1248\/cpb.16.1860","article-title":"Lycoricidinol\nand Lycoricidine, New\nPlant-growth Regulators in the Bulbs of Lycoris radiata HERB","volume":"16","author":"Okamoto","year":"1968","journal-title":"Chemical and Pharmaceutical Bulletin"},{"issue":"6","key":"2026100909103699700_cit33","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1248\/cpb.31.2146","article-title":"Antifeedants\nfor the larvae of the\nyellow butterfly, Eurema hecabe mandarina, in Lycoris radiata","volume":"31","author":"Numata","year":"1983","journal-title":"Chemical and Pharmaceutical Bulletin"},{"issue":"2","key":"2026100909103699700_cit34","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/0031-9422(89)80061-5","article-title":"Isocarbostyril\nalkaloids from Haemanthus kalbreyeri","volume":"28","author":"Ghosal","year":"1989","journal-title":"Phytochemistry"},{"issue":"1","key":"2026100909103699700_cit35","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1021\/np50115a004","article-title":"Antineoplastic Agents,\n294. Variations in the Formation of Pancratistatin and Related Isocarbostyrils\nin Hymenocallis littoralis","volume":"58","author":"Pettit","year":"1995","journal-title":"J. Nat. Prod."},{"issue":"5","key":"2026100909103699700_cit36","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1021\/np50119a017","article-title":"Antineoplastic Agents, 301. An investigation\nof the Amaryllidaceae genus Hymenocallis","volume":"58","author":"Pettit","year":"1995","journal-title":"J.\nNat. Prod."},{"issue":"8","key":"2026100909103699700_cit37","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1021\/np0402367","article-title":"Antineoplastic\nAgents. 553. The Texas Grasshopper Brachystola magna","volume":"68","author":"Pettit","year":"2005","journal-title":"J. Nat. Prod."},{"issue":"6","key":"2026100909103699700_cit38","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1021\/acs.jnatprod.8b00218","article-title":"Isolation,\nSynthesis, and Semisynthesis of Amaryllidaceae\nConstituents from Narcissus and Galanthus sp.: De Novo Total Synthesis\nof 2-epi-Narciclasine","volume":"81","author":"Borra","year":"2018","journal-title":"J. Nat. Prod."},{"issue":"1","key":"2026100909103699700_cit39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1593\/tlo.08100","article-title":"Amaryllidaceae\nisocarbostyril alkaloids and their derivatives as promising antitumor\nagents","volume":"1","author":"Ingrassia","year":"2008","journal-title":"Translational Oncology"},{"key":"2026100909103699700_cit40","first-page":"348","article-title":"An improved\nmethod for the large-scale\npreparation of lycorine","volume":"9","author":"Evidente","year":"1984","journal-title":"Chem. Ind."},{"key":"2026100909103699700_cit41","first-page":"1","article-title":"Estrazione\ndi licorina da bulbi di\nStembergia lutea Ker-Gawl al termine del periodo vegetative","volume":"5","author":"Amico","year":"1967","journal-title":"Flora salutaris"},{"issue":"1","key":"2026100909103699700_cit42","first-page":"9","article-title":"The Alkaloids\nof Sternbergia Lutea Ker. (Amaryllidaceae)","volume":"1","author":"Phokas","year":"1971","journal-title":"Farmakeftikon Deltion (E\u0301dition Scientifique)"},{"key":"2026100909103699700_cit43","first-page":"8353","article-title":"Investigation\nof the alkaloids of the genus Stembergia","volume":"125","author":"Prosskumina","year":"1954","journal-title":"Chemisches\nZentralblatt"},{"issue":"4","key":"2026100909103699700_cit44","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1021\/np50064a020","article-title":"Four New Crinine-Type Alkaloids from\nSternbergia Species","volume":"52","author":"Pabuc\u0327c\u0327uoglu","year":"1989","journal-title":"J. Nat. Prod."},{"key":"2026100909103699700_cit45","doi-asserted-by":"publisher","first-page":"31","DOI":"10.9734\/ajacr\/2022\/v11i230252","article-title":"Isolation\nand Characterisation of Haemanthamine Alkaloid from Daffolis Extract\nusing NMR and Mass Spectroscopic Techniques","author":"Ogbu","year":"2022","journal-title":"Asian Journal of Applied Chemistry Research"},{"issue":"7","key":"2026100909103699700_cit46","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1038\/s41375-018-0364-x","article-title":"Creating novel translation inhibitors to target pro-survival\nproteins in chronic lymphocytic leukemia","volume":"33","author":"Chen","year":"2019","journal-title":"Leukemia"},{"issue":"9","key":"2026100909103699700_cit47","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1038\/s41375-021-01181-w","article-title":"BET proteolysis targeted chimera-based therapy of novel\nmodels of Richter Transformation-diffuse large B-cell lymphoma","volume":"35","author":"Fiskus","year":"2021","journal-title":"Leukemia"},{"issue":"6","key":"2026100909103699700_cit48","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1038\/s41375-022-01553-w","article-title":"Cyclin-dependent kinase\ninhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and\nsynergizes with venetoclax in primary chronic lymphocytic leukemia\ncells","volume":"36","author":"Chen","year":"2022","journal-title":"Leukemia"},{"key":"2026100909103699700_cit49","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis\nof dose-effect relationships:\nthe combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Advances in Enzyme Regulation"},{"issue":"3","key":"2026100909103699700_cit50","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical\nbasis, experimental design, and computerized simulation of synergism\nand antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. 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