{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:00:45Z","timestamp":1780401645616,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T00:00:00Z","timestamp":1695427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program through the National Research Foundation of Korea","award":["NRF-2021R1I1A3050093"],"award-info":[{"award-number":["NRF-2021R1I1A3050093"]}]},{"name":"Brain Korea 21 Project","award":["NRF-2021R1I1A3050093"],"award-info":[{"award-number":["NRF-2021R1I1A3050093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer and has a poor prognosis. As standardized TNBC treatment regimens cause drug resistance and tumor recurrence, the development of new TNBC treatment strategies is urgently required. Bufotalin is a bufadienolide isolated from the skin and parotid venom glands of the toad Bufo gargarizan, and has several pharmacological properties, including antiviral, anti-inflammatory, and anticancer activities. However, the anticancer effect and underlying molecular mechanisms of action of bufotalin in TNBC have not been fully studied. In the current study, we investigated the effects of bufotalin on the growth and metastasis of MDA-MB-231 and HCC1937 TNBC cells. Bufotalin potently inhibited the proliferation of both TNBC cell lines by promoting cell cycle arrest and caspase-mediated apoptosis. Furthermore, bufotalin effectively suppressed the migration and invasion of both TNBC cell lines by regulating the expression of key epithelial-mesenchymal transition (EMT) biomarkers, matrix metalloproteinases (MMPs), and integrin \u03b16. Notably, the anticancer effect of bufotalin in TNBC cells was associated with the downregulation of the signal transducer and activator of the transcription 3 (STAT3) signaling pathway. Collectively, our results suggest that the natural compound bufotalin may exert antiproliferative and antimetastatic activities in TNBC cells by modulating the apoptotic pathway and the STAT3\/EMT axis.<\/jats:p>","DOI":"10.3390\/molecules28196783","type":"journal-article","created":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T10:48:31Z","timestamp":1695552511000},"page":"6783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Bufotalin Suppresses Proliferation and Metastasis of Triple-Negative Breast Cancer Cells by Promoting Apoptosis and Inhibiting the STAT3\/EMT Axis"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1556-817X","authenticated-orcid":false,"given":"So Jin","family":"Park","sequence":"first","affiliation":[{"name":"Department of Life Science and Biochemical Engineering, Graduate School, Sun Moon University, Asan 31460, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3145-9300","authenticated-orcid":false,"given":"Hye Jin","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Life Science and Biochemical Engineering, Graduate School, Sun Moon University, Asan 31460, Republic of Korea"},{"name":"Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, Republic of Korea"},{"name":"Genome-Based BioIT Convergence Institute, Sun Moon University, Asan 31460, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.breast.2022.08.010","article-title":"Current and future burden of breast cancer: Global statistics for 2020 and 2040","volume":"66","author":"Arnold","year":"2022","journal-title":"Breast"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5901","DOI":"10.2147\/IJGM.S370351","article-title":"Treatment for triple-negative breast cancer: An umbrella review of meta-analyses","volume":"15","author":"Yin","year":"2022","journal-title":"Int. J. Gen. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3121\/cmr.2008.825","article-title":"Breast cancer subtypes based on ER\/PR and Her2 expression: Comparison of clinicopathologic features and survival","volume":"7","author":"Onitilo","year":"2009","journal-title":"Clin. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1007\/s00432-022-04189-6","article-title":"Triple negative breast cancer: Approved treatment options and their mechanisms of action","volume":"149","author":"Mandapati","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_5","first-page":"93","article-title":"Triple-negative breast cancer: Treatment challenges and solutions","volume":"8","author":"Collignon","year":"2016","journal-title":"Breast Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"600573","DOI":"10.3389\/fonc.2020.600573","article-title":"Immune checkpoint inhibitors in triple negative breast cancer treatment: Promising future prospects","volume":"10","author":"Thomas","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1080\/13543784.2022.2067527","article-title":"PARP inhibitors as single agents and in combination therapy: The most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers","volume":"31","author":"Luo","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","article-title":"Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease","volume":"13","author":"Bianchini","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/path.1706","article-title":"Molecular mechanisms of drug resistance","volume":"205","author":"Longley","year":"2005","journal-title":"J. Pathol."},{"key":"ref_10","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_11","first-page":"87","article-title":"The biology of cell death in tumours","volume":"6","author":"Cooper","year":"1973","journal-title":"Cell Tissue Kinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1006\/excr.2000.4838","article-title":"Induction of apoptosis by cancer chemotherapy","volume":"256","author":"Kaufmann","year":"2000","journal-title":"Exp. Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41580-018-0089-8","article-title":"Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins","volume":"20","author":"Singh","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13058-020-01296-5","article-title":"Triple-negative breast cancer molecular subtyping and treatment progress","volume":"22","author":"Yin","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wu, Q., Siddharth, S., and Sharma, D. (2021). Triple negative breast cancer: A mountain yet to be scaled despite the triumphs. Cancers, 13.","DOI":"10.3390\/cancers13153697"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eabn7571","DOI":"10.1126\/scitranslmed.abn7571","article-title":"Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin","volume":"14","author":"Grasset","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.tcb.2018.12.001","article-title":"EMT transition states during tumor progression and metastasis","volume":"29","author":"Pastushenko","year":"2019","journal-title":"Trends Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s13046-019-1206-z","article-title":"STAT3 as a potential therapeutic target in triple negative breast cancer: A systematic review","volume":"38","author":"Qin","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12195-021-00694-9","article-title":"Epithelial-to-mesenchymal transition signaling pathways responsible for breast cancer metastasis","volume":"15","author":"Buyuk","year":"2021","journal-title":"Cell. Mol. Bioeng."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1002\/jcp.25797","article-title":"Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis","volume":"232","author":"Chen","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1002\/rcm.1989","article-title":"Analysis of bufadienolides in the Chinese drug ChanSu by high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry","volume":"19","author":"Ye","year":"2005","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejphar.2012.06.045","article-title":"Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2\/M cell cycle arrest and apoptosis","volume":"692","author":"Zhang","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1007\/s00210-020-01817-1","article-title":"Bufotalin ameliorates experimental Sj\u00f6gren\u2019s syndrome development by inhibiting Th17 generation","volume":"393","author":"Huang","year":"2020","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jin, Y.H., Jeon, S., Lee, J., Kim, S., Jang, M.S., Park, C.M., Song, J.H., Kim, H.R., and Kwon, S. (2021). Broad spectrum antiviral properties of cardiotonic steroids used as potential therapeutics for emerging coronavirus infections. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111839"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1014637","DOI":"10.3389\/fonc.2022.1014637","article-title":"A research update on the antitumor effects of active components of Chinese medicine ChanSu","volume":"12","author":"Jia","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/jf802769g","article-title":"Involvement of caspases and apoptosis-inducing factor in bufotalin-induced apoptosis of Hep 3B cells","volume":"57","author":"Su","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","first-page":"2409","article-title":"Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells","volume":"41","author":"Pan","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_28","first-page":"1566","article-title":"Bufadienolides induce p53-mediated apoptosis in esophageal squamous cell carcinoma cells in vitro and in vivo","volume":"15","author":"Lin","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.freeradbiomed.2022.01.009","article-title":"Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4","volume":"180","author":"Zhang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1091\/mbc.01-05-0272","article-title":"Activation and caspase-mediated inhibition of PARP: A molecular switch between fibroblast necrosis and apoptosis in death receptor signaling","volume":"13","author":"Los","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1073\/pnas.98.4.1853","article-title":"Integrin activation controls metastasis in human breast cancer","volume":"98","author":"Smith","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","first-page":"5865","article-title":"The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis","volume":"14","author":"Li","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"El-Seedi, H.R., Yosri, N., El-Aarag, B., Mahmoud, S.H., Zayed, A., Du, M., Saeed, A., Musharraf, S.G., El-Garawani, I.M., and Habib, M.R. (2022). Chemistry and the potential antiviral, anticancer, and anti-inflammatory activities of cardiotonic steroids derived from toads. Molecules, 27.","DOI":"10.3390\/molecules27196586"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1093\/carcin\/bgy039","article-title":"Bufalin inhibits human breast cancer tumorigenesis by inducing cell death through the ROS-mediated RIP1\/RIP3\/PARP-1 pathways","volume":"39","author":"Li","year":"2018","journal-title":"Carcinogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s10495-011-0573-5","article-title":"Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3\/Mcl-1 pathway","volume":"16","author":"Dong","year":"2011","journal-title":"Apoptosis"},{"key":"ref_36","first-page":"4256","article-title":"Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF-7 breast cancer cells","volume":"19","author":"Li","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1080\/14786419.2017.1315575","article-title":"Anti-proliferative and pro-apoptotic effects of cinobufagin on human breast cancer MCF-7 cells and its molecular mechanism","volume":"32","author":"Zhu","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"ref_38","first-page":"7837","article-title":"Telocinobufagin inhibits the epithelial-mesenchymal transition of breast cancer cells through the phosphoinositide 3-kinase\/protein kinase B\/extracellular signal-regulated kinase\/Snail signaling pathway","volume":"15","author":"Gao","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1016\/j.apsb.2021.01.004","article-title":"Integrins as attractive targets for cancer therapeutics","volume":"11","author":"Li","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/sj.onc.1206158","article-title":"Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells","volume":"22","author":"Zhang","year":"2003","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tolomeo, M., and Cascio, A. (2021). The multifaced role of STAT3 in cancer and its implication for anticancer therapy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020603"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24772","DOI":"10.3390\/ijms161024772","article-title":"Elevated STAT3 signaling-mediated upregulation of MMP-2\/9 confers enhanced invasion ability in multidrug-resistant breast cancer cells","volume":"16","author":"Zhang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.3389\/fphar.2019.01195","article-title":"Inhibition of Stat3 signaling pathway by natural product pectolinarigenin attenuates breast cancer metastasis","volume":"10","author":"Li","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12964-020-00577-y","article-title":"Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3","volume":"18","author":"Visavadiya","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"112178","DOI":"10.1016\/j.jep.2019.112178","article-title":"Metabolites from Bufo gargarizans (Cantor, 1842): A review of traditional uses, pharmacological activity, toxicity and quality control","volume":"246","author":"Zhan","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100007","DOI":"10.1016\/j.prmcm.2021.100007","article-title":"Chansu improves the respiratory function of severe COVID-19 patients","volume":"1","author":"Hu","year":"2021","journal-title":"Pharmacol. Res. Mod. Chin. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cho, H.J., and Jung, H.J. (2023). Cyclophilin A inhibitors suppress proliferation and induce apoptosis of MKN45 gastric cancer stem-like cells by regulating CypA\/CD147-mediated signaling pathway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054734"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Han, J.M., Kim, H.L., and Jung, H.J. (2021). Ampelopsin inhibits cell proliferation and induces apoptosis in HL60 and K562 leukemia cells by downregulating AKT and NF-\u03baB signaling pathways. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084265"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Han, J.M., Choi, Y.S., Dhakal, D., Sohng, J.K., and Jung, H.J. (2020). Novel nargenicin A1 analog inhibits angiogenesis by downregulating the endothelial VEGF\/VEGFR2 signaling and tumoral HIF-1\u03b1\/VEGF pathway. Biomedicines, 8.","DOI":"10.3390\/biomedicines8080252"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/19\/6783\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:56:56Z","timestamp":1760129816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/19\/6783"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,23]]},"references-count":49,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["molecules28196783"],"URL":"https:\/\/doi.org\/10.3390\/molecules28196783","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,23]]}}}