{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:29:23Z","timestamp":1773098963999,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Naturally occurring coumarins are bioactive compounds widely used in Asian traditional medicine. They have been shown to inhibit proliferation, induce apoptosis, and\/or enhance the cytotoxicity of currently used drugs against a variety of cancer cell types. The aim of our study was to examine the antiproliferative activity of different linear furanocoumarins on human rhabdomyosarcoma, lung, and larynx cancer cell lines, and dissolve their cellular mechanism of action. The coumarins were isolated from fruits of Angelica archangelica L. or Pastinaca sativa L., and separated using high-performance counter-current chromatography (HPCCC). The identity and purity of isolated compounds were confirmed by HPLC-DAD and NMR analyses. Cell viability and toxicity assessments were performed by means of methylthiazolyldiphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, respectively. Induction of apoptosis and cell cycle progression were measured using flow cytometry analysis. qPCR method was applied to detect changes in gene expression. Linear furanocoumarins in a dose-dependent manner inhibited proliferation of cancer cells with diverse activity regarding compounds and cancer cell type specificity. Imperatorin (IMP) exhibited the most potent growth inhibitory effects against human rhabdomyosarcoma and larynx cancer cell lines owing to inhibition of the cell cycle progression connected with specific changes in gene expression, including CDKN1A. As there are no specific chemotherapy treatments dedicated to laryngeal squamous cell carcinoma and rhabdomyosarcoma, and IMP seems to be non-toxic for normal cells, our results could open a new direction in the search for effective anti-cancer agents.<\/jats:p>","DOI":"10.3390\/molecules25092046","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T01:24:18Z","timestamp":1588123458000},"page":"2046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Imperatorin as a Promising Chemotherapeutic Agent against Human Larynx Cancer and Rhabdomyosarcoma Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3823-1467","authenticated-orcid":false,"given":"Aneta","family":"Grabarska","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9313-5929","authenticated-orcid":false,"given":"Krystyna","family":"Skalicka-Wo\u017aniak","sequence":"additional","affiliation":[{"name":"Independent Laboratory of Natural Products Chemistry, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Kie\u0142bus","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6248-0930","authenticated-orcid":false,"given":"Magdalena","family":"Dmoszy\u0144ska-Graniczka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Miziak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justyna","family":"Szumi\u0142o","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathomorphology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Nowosadzka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krystyna","family":"Kowalczuk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherief","family":"Khalifa","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gulf Medical University, P.O. Box 4184 Ajman, UAE"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolanta","family":"Smok-Kalwat","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janusz","family":"Klatka","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Laryngological Oncology, Medical University of Lublin, 20-954 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Kupisz","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Laryngological Oncology, Medical University of Lublin, 20-954 Lublin, Poland"},{"name":"Department of Otolaryngology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Polberg","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, MSWiA Hospital, 20-331 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9794-802X","authenticated-orcid":false,"given":"Adolfo","family":"Rivero-M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"},{"name":"Faculty of Science and Engineering, Cell Biology, \u00c5boAkademi University, 20520 Turku, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-394X","authenticated-orcid":false,"given":"Andrzej","family":"Stepulak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"ref_1","first-page":"233","article-title":"Rutagraveolens extract induces DNA damage pathways and blocks Akt activation to inhibit cancer cell proliferation and survival","volume":"31","author":"Fadlalla","year":"2011","journal-title":"Anticancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.2174\/092986708786242877","article-title":"A review of coumarin derivatives in pharmacotherapy of breast cancer","volume":"15","author":"Musa","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_3","first-page":"129","article-title":"Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines","volume":"25","author":"Guo","year":"2004","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_4","first-page":"1223","article-title":"Natural and synthetic coumarins as potential anticancer agents","volume":"7","author":"Klenkar","year":"2015","journal-title":"J. Chem. Pharm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"348","DOI":"10.5306\/wjco.v5.i3.348","article-title":"Effects of psoralens as anti-tumoral agents in breast cancer cells","volume":"5","author":"Panno","year":"2014","journal-title":"World J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3390\/90300050","article-title":"New synthetic routes to furocoumarins and their analogs: A review","volume":"9","author":"Traven","year":"2004","journal-title":"Molecules"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Shalaby, N.M., Abd-Alla, H.I., Aly, H.F., Albalawy, M.A., Shaker, K.H., and Bouajila, J. (2014). Preliminary in vitro and in vivo evaluation of antidiabetic activity of Ducrosia anethifolia Boiss. And its linear furanocoumarins. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/480545"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S1734-1140(10)70387-X","article-title":"Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: A comparative study","volume":"62","author":"Luszczki","year":"2010","journal-title":"Pharmacol. Rep."},{"key":"ref_9","first-page":"431","article-title":"Purification and anticonvulsant activity of xanthotoxin (8-methoxypsolaren)","volume":"9","author":"Zagaja","year":"2014","journal-title":"Cent. Eur. J. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jep.2017.06.010","article-title":"8-methoxypsoralen reduces Akt phosphorylation, induces intrinsic and extrinsic apoptotic pathways, and suppresses cell growth of SK-N-AS neuroblastoma and SW620 metastatic colon cancer cells","volume":"207","author":"Bartnik","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1365-2184.2012.00816.x","article-title":"Evaluation of phototoxic potential of aerial components of the fig tree against human melanoma","volume":"45","author":"Conforti","year":"2012","journal-title":"Cell Prolif."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000430360","article-title":"8-methoxypsoralen induces intrinsic apoptosis in HepG2 cells: Involvement of reactive oxygen species generation and ERK1\/2 pathway inhibition","volume":"37","author":"Yang","year":"2015","journal-title":"Cell Physiol. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2174\/156800909788486786","article-title":"Evidence that bergapten, independently of its photoactivation, enhances p53 gene expression and induces apoptosis in human breast cancer cells","volume":"9","author":"Panno","year":"2009","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s13277-015-3591-z","article-title":"Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy","volume":"37","author":"Hu","year":"2016","journal-title":"Tumour. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.canlet.2014.08.002","article-title":"Bergamottin, a natural furanocoumarin obtained from grapefruit juice induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells","volume":"354","author":"Kim","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1248\/bpb.b15-00957","article-title":"Effects of psoralen as an anti-tumor agent in human breast cancer MCF-7\/ADR cells","volume":"39","author":"Wang","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.phymed.2014.03.008","article-title":"Psoralen reverses docetaxel-induced multidrug resistance in A549\/D16 human lung cancer cells lines","volume":"21","author":"Hsieh","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s11101-014-9348-2","article-title":"Counter-current chromatography for the separation of terpenoids: A comprehensive review with respect to the solvent systems employed","volume":"13","author":"Garrard","year":"2014","journal-title":"Phytochem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.2174\/0929867043365189","article-title":"Natural medicine: The genus Angelica","volume":"11","author":"Sarker","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zou, Y., Sarem, M., Xiang, S., Hu, H., Xu, W., and Shastri, V.P. (2019). Autophagy inhibition enhances matrine derivative MASM induced apoptosis in cancer cells via a mechanism involving reactive oxygen species-mediated PI3K\/Akt\/mTOR and Erk\/p38 signaling. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6199-7"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s11418-016-0992-2","article-title":"Screening of promising chemotherapeutic candidates from plants extracts","volume":"70","author":"Kinjo","year":"2016","journal-title":"J. Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s11658-019-0164-y","article-title":"Progress in research on paclitaxel and tumor immunotherapy","volume":"24","author":"Zhu","year":"2019","journal-title":"Cell Mol. Biol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"186","DOI":"10.2174\/1567201812666150702102800","article-title":"A review on chemical profile of coumarins and their therapeutic role in the treatment of cancer","volume":"13","author":"Gurupadayya","year":"2016","journal-title":"Curr. Drug Deliv."},{"key":"ref_25","first-page":"4347","article-title":"7-substituted coumarins inhibit proliferation and migration of laryngeal cancer cells in vitro","volume":"33","author":"Kielbus","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_26","first-page":"6473","article-title":"Osthole induces apoptosis, suppresses cell-cycle progression and proliferation of cancer cells","volume":"34","author":"Jarzab","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1007\/s11418-016-1046-5","article-title":"Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia\/lymphoma (v): Coumarins and alkaloids from Boenninghausenia japonica and Ruta graveolens","volume":"71","author":"Nakano","year":"2017","journal-title":"J. Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1515\/znc-2004-7-813","article-title":"Antiproliferative effect of Angelica archangelica fruits","volume":"59","author":"Sigurdsson","year":"2004","journal-title":"Z Naturforsch C"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s11101-016-9456-2","article-title":"Imperatorin-pharmacological meaning and analytical clues: Profound investigation","volume":"15","author":"Koziol","year":"2016","journal-title":"Phytochem. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s11010-014-2032-4","article-title":"Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep-2 cells","volume":"392","author":"Badziul","year":"2014","journal-title":"Mol. Cell Biochem."},{"key":"ref_31","first-page":"195","article-title":"Establishment and preliminary characterization of two cell lines derived from larynx carcinoma","volume":"40","author":"Rzeski","year":"2002","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.3892\/or.2017.5581","article-title":"Imperatorin efficiently blocks TNF-alpha-mediated activation of ROS\/PI3K\/Akt\/NF-kappaB pathway","volume":"37","author":"Wang","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.3892\/or.2016.4586","article-title":"Imperatorin exhibits anticancer activities in human colon cancer cells via the caspase cascade","volume":"35","author":"Zheng","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3389\/fonc.2013.00183","article-title":"Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: Utility and pitfalls","volume":"3","author":"Hinson","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_35","first-page":"2243","article-title":"Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma","volume":"52","author":"Felix","year":"1992","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/jmcb\/mjy072","article-title":"Mutant p53 in cancer therapy-the barrier or the path","volume":"11","author":"Zhou","year":"2019","journal-title":"J. Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jchromb.2013.11.050","article-title":"Simultaneous determination of imperatorin and its metabolite xanthotoxol in rat plasma by using HPLC-ESI-MS coupled with hollow fiber liquid phase microextraction","volume":"945\u2013946","author":"Zhang","year":"2014","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/bmc.3100","article-title":"Simultaneous determination of imperatorin and its metabolites in vitro and in vivo by a GC-MS method: Application to a bioavailability and protein binding ability study in rat plasma","volume":"28","author":"Zhao","year":"2014","journal-title":"Biomed. Chromatogr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4216","DOI":"10.1002\/jssc.201500840","article-title":"Separation and simultaneous quantification of nine furanocoumarins from Radix Angelicae dahuricae using liquid chromatography with tandem mass spectrometry for bioavailability determination in rats","volume":"38","author":"Chen","year":"2015","journal-title":"J. Sep. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.phymed.2016.06.015","article-title":"Simultaneous determination and pharmacokinetics of sixteen Angelicae dahurica coumarins in vivo by LC-ESI-MS\/MS following oral delivery in rats","volume":"23","author":"Zhao","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3563","DOI":"10.1111\/bph.14424","article-title":"Activating the pregnane X receptor by imperatorin attenuates dextran sulphate sodium-induced colitis in mice","volume":"175","author":"Liu","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lee, K., Shin, M.S., Ham, I., and Choi, H.Y. (2015). Investigation of the mechanisms of Angelica dahurica root extract-induced vasorelaxation in isolated rat aortic rings. BMC Complement. Altern Med., 15.","DOI":"10.1186\/s12906-015-0889-8"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.mayocp.2015.12.017","article-title":"Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment","volume":"91","author":"Marur","year":"2016","journal-title":"Mayo Clin. Proc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.physbeh.2013.08.019","article-title":"Effects of imperatorin on nicotine-induced anxiety- and memory-related responses and oxidative stress in mice","volume":"122","author":"Budzynska","year":"2013","journal-title":"Physiol. Behav."},{"key":"ref_45","first-page":"99","article-title":"A simplified method of evaluating dose-effect experiments","volume":"96","author":"Litchfield","year":"1949","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/9\/2046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:24:00Z","timestamp":1760361840000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/9\/2046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,28]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["molecules25092046"],"URL":"https:\/\/doi.org\/10.3390\/molecules25092046","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,28]]}}}