{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:01:11Z","timestamp":1789563671097,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T00:00:00Z","timestamp":1746316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)","award":["RS-2022-00166390"],"award-info":[{"award-number":["RS-2022-00166390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Breast cancer remains the most prevalent malignancy among women worldwide. Innovative therapies are essential to address its diverse subtypes and treatment resistance. Scorpion venom and its bioactive proteins have gained attention as potential anticancer agents owing to their multitargeted cellular effects. This review systematically evaluates their anticancer properties and mechanisms in breast cancer, highlighting therapeutic potential. Methods: A systematic search was conducted in five databases (PubMed, Science Direct, EMBASE, OVID, and KISS) up to September 2024. Only in vitro studies using breast cancer cell lines and investigating scorpion venom or its bioactive proteins were included. Extracted data covered study characteristics, intervention types, control groups, dose range, duration, and key outcomes. Results: In total, 19 studies met the eligibility criteria. Crude scorpion venom showed broad cytotoxicity against hormone receptor-positive, triple-negative, and HER2-positive breast cancer subtypes. The primary mechanisms included apoptosis induction, DNA fragmentation, oxidative stress modulation, and cell cycle regulation. Bioactive proteins, such as chlorotoxin (CTX) and Neopladine 1\/2, exhibited selective anticancer effects by targeting signaling pathways, inhibiting migration and invasion, and promoting apoptosis. Conclusion: These findings support scorpion venom\u2019s potential as a multitargeted anticancer agent. The complementary actions of crude venom and its proteins highlight their promise for combination therapies. Further research is needed to clarify their synergistic interactions and optimize preclinical and clinical applications.<\/jats:p>","DOI":"10.3390\/jcm14093181","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T20:10:27Z","timestamp":1746389427000},"page":"3181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Systematic Review of the Antitumor Activities and Mechanisms of Scorpion Venom on Human Breast Cancer Cells Lines (In Vitro Study)"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-1801","authenticated-orcid":false,"given":"Na-Yoen","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Korean Medicine, Ga-Chon University, Seongnam-si 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0366-1707","authenticated-orcid":false,"given":"Hyun-Kyung","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Education, College of Korean Medicine, Dongguk University, Gyeongju-si 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4323-278X","authenticated-orcid":false,"given":"Jang-Kyung","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan-si 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3322\/caac.21235","article-title":"Cancer treatment and survivorship statistics, 2014","volume":"64","author":"DeSantis","year":"2014","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kwon, N.Y., Sung, S.H., Sung, H.K., and Park, J.K. (2022). Anticancer activity of bee venom components against breast cancer. Toxins, 14.","DOI":"10.3390\/toxins14070460"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"R92","DOI":"10.1186\/bcr3493","article-title":"Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer","volume":"15","author":"Eccles","year":"2013","journal-title":"Breast Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.ejca.2013.09.002","article-title":"Recent trends in incidence of five common cancers in 26 European countries since 1988: Analysis of the European Cancer Observatory","volume":"51","author":"Arnold","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_5","first-page":"104","article-title":"Synergistic effects induced by combined treatments of aqueous extract of propolis and venom","volume":"89","author":"Drigla","year":"2016","journal-title":"Clujul Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Anampa, J., Makower, D., and Sparano, J.A. (2015). Progress in adjuvant chemotherapy for breast cancer: An overview. BMC Med., 13.","DOI":"10.1186\/s12916-015-0439-8"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/jnci\/93.13.979","article-title":"National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1\u20133, 2000","volume":"93","author":"Eifel","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Daniluk, K., Kutwin, M., Grodzik, M., Wierzbicki, M., Strojny, B., Szczepaniak, J., Ba\u0142aban, J., Sosnowska, M., Chwalibog, A., and Sawosz, E. (2019). Use of selected carbon nanoparticles as melittin carriers for MCF-7 and MDA-MB-231 human breast cancer cells. Materials, 13.","DOI":"10.3390\/ma13010090"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.4103\/jcrt.JCRT_154_19","article-title":"Health-related quality of life in patients with breast cancer surgery and undergoing chemotherapy in Ahmednagar district","volume":"17","author":"Kshirsagar","year":"2021","journal-title":"J. Cancer Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.biopha.2018.06.105","article-title":"Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells","volume":"105","author":"Khamis","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hwang, S.I., Yoon, Y.J., Sung, S.H., Ha, K.T., and Park, J.K. (2021). Toxic animal-based medicinal materials can be effective in treating endometriosis: A scoping review. Toxins, 13.","DOI":"10.3390\/toxins13020145"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2174\/1568026619666181221120817","article-title":"Animal venoms have potential to treat cancer","volume":"18","author":"Chatterjee","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Upadhya, R.K. (2018). Use of animal venom peptides\/toxins in cancer therapeutics. Curr. Trends Biomed. Eng. Biosci., 16.","DOI":"10.19080\/CTBEB.2018.16.555945."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.toxicon.2016.09.005","article-title":"Medical application of scorpion venom to breast cancer: A mini-review","volume":"122","author":"Eshun","year":"2016","journal-title":"Toxicon"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.toxicon.2011.01.002","article-title":"Arthropod venoms and cancer","volume":"57","author":"Heinen","year":"2011","journal-title":"Toxicon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"702","DOI":"10.2174\/0929866525666180614114307","article-title":"Scorpion venom peptides as a potential source for human drug candidates","volume":"25","author":"Uzair","year":"2018","journal-title":"Protein Pept. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1039\/C8TB00038G","article-title":"The effects of surface charge on the intra-tumor penetration of drug delivery vehicles with tumor progression","volume":"6","author":"Han","year":"2018","journal-title":"J. Mater. Chem. B"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.4103\/1735-5362.305193","article-title":"Development and characterization of a nano-drug delivery system containing vasaka phospholipid complex to improve bioavailability using quality by design approach","volume":"16","author":"Nandhini","year":"2021","journal-title":"Res. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Due\u00f1as-Cuellar, R.A., Santana, C.J.C., Magalh\u00e3es, A.C.M., Pires, O.R., Fontes, W., and Castro, M.S. (2020). Scorpion toxins and ion channels: Potential applications in cancer therapy. Toxins, 12.","DOI":"10.3390\/toxins12050326"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S0041-0101(02)00142-3","article-title":"An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch","volume":"40","author":"Goudet","year":"2002","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.tiv.2011.04.030","article-title":"Thymoquinone from Nigella sativa was more potent than cisplatin in eliminating of SiHa cells via apoptosis with down-regulation of Bcl-2 protein","volume":"25","author":"Ng","year":"2011","journal-title":"Toxicol. In Vitro"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"881","DOI":"10.2147\/DDDT.S231008","article-title":"Pleiotropic anticancer properties of scorpion venom peptides: Rhopalurus princeps venom as an anticancer agent","volume":"14","author":"Mikaelian","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41568-021-00378-6","article-title":"Cancer metabolism: Looking forward","volume":"21","author":"Chandel","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Park, J.H., Pyun, W.Y., and Park, H.W. (2020). Cancer metabolism: Phenotype, signaling and therapeutic targets. Cells, 9.","DOI":"10.3390\/cells9102308"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: New dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/j.toxicon.2010.09.008","article-title":"Apoptogenic peptides from Tityus discrepans scorpion venom acting against the SKBR3 breast cancer cell line","volume":"56","author":"Rosales","year":"2010","journal-title":"Toxicon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1678-9199-20-48","article-title":"Characterization of Leiurus abdullahbayrami (Scorpiones: Buthidae) venom: Peptide profile, cytotoxicity and antimicrobial activity","volume":"20","author":"Kunt","year":"2014","journal-title":"J. Venom. Anim. Toxins Incl. Trop. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"345","DOI":"10.4314\/tjpr.v20i2.18","article-title":"Cytotoxic effect of Leurius quinquestratus (scorpion) venom in different human cancer cell lines in vitro","volume":"20","author":"Salama","year":"2021","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1007\/s12029-021-00762-3","article-title":"Evaluation of human Wharton\u2019s jelly-derived mesenchymal stem cells conditioning medium (hWJ-MSCs-CM) or scorpion venom breast cancer cell line in vitro","volume":"53","author":"Said","year":"2022","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.3892\/ol.2015.4036","article-title":"In vitro analysis of the anticancer properties of scorpion venom in colorectal and breast cancer cell lines","volume":"11","author":"Islam","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1186\/s40064-016-2269-3","article-title":"In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model","volume":"5","author":"Salem","year":"2016","journal-title":"SpringerPlus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.4314\/ajtcam.v11i5.17","article-title":"Inhibition effects of scorpion venom extracts (Buthus matensii Karsch) on the growth of human breast cancer MCF-7 cells","volume":"11","author":"Li","year":"2014","journal-title":"Afr. J. Tradit. Complement. Altern. Med."},{"key":"ref_35","first-page":"192","article-title":"In-vitro study of Hottentotta schach crude venom anticancer effects on MCF-7 and Vero cell lines","volume":"19","author":"Dezianian","year":"2020","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_36","first-page":"759","article-title":"Rhopalurus junceus scorpion venom induces antitumor effect in vitro and in vivo against a murine mammary adenocarcinoma model","volume":"22","author":"Garlobo","year":"2019","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_37","first-page":"9","article-title":"Rhopalurus junceus scorpion venom induces apoptosis in the triple negative human breast cancer cell line MDA-MB-231","volume":"8","year":"2017","journal-title":"J. Venom. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"537","DOI":"10.4103\/0253-7613.190742","article-title":"Scorpion (Androctonus bicolor) venom exhibits cytotoxicity and induces cell cycle arrest and apoptosis in breast and colorectal cancer cell lines","volume":"48","author":"Riyasdeen","year":"2016","journal-title":"Indian. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.yexmp.2011.04.008","article-title":"Scorpion (Androctonus crassicauda) venom limits growth of transformed cells (SH-SY5Y and MCF-7) by cytotoxicity and cell cycle arrest","volume":"91","author":"Zargan","year":"2011","journal-title":"Exp. Mol. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.tiv.2011.09.002","article-title":"Scorpion venom (Odontobuthus doriae) induces apoptosis by depolarization of mitochondria and reduces S-phase population in human breast cancer cells (MCF-7)","volume":"25","author":"Zargan","year":"2011","journal-title":"Toxicol. In Vitro"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2156587217751796","DOI":"10.1177\/2156587217751796","article-title":"Scorpion venom causes apoptosis by increasing reactive oxygen species and cell cycle arrest in MDA-MB-231 and HCT-8 cancer cell lines","volume":"23","author":"Riyasdeen","year":"2018","journal-title":"J. Evid. Based Integr. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1177\/1534735417704949","article-title":"Scorpion venom causes upregulation of p53 and downregulation of Bcl-xL and BID protein expression by modulating signaling proteins ERK1\/2 and STAT3, and DNA damage in breast and colorectal cancer cell lines","volume":"17","author":"Riyasdeen","year":"2018","journal-title":"Integr. Cancer Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/cbdd.13123","article-title":"Anticancer activity of VmCT1 analogs against MCF-7 cells","volume":"91","author":"Pedron","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rezaei, A., Asgari, S., Komijani, S., Sadat, S.N., Sabatier, J.M., Nasrabadi, D., Pooshang Bagheri, K., Shahbazzadeh, D., Akbari Eidgahi, M.R., and De Waard, M. (2022). Discovery of leptulipin, a new anticancer protein from the Iranian scorpion, Hemiscorpius Lepturus. Molecules, 27.","DOI":"10.3390\/molecules27072056"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1002\/cam4.2019","article-title":"Chlorotoxin targets ER\u03b1\/VASP signaling pathway to combat breast cancer","volume":"8","author":"Wang","year":"2019","journal-title":"Cancer Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.cbpc.2008.06.003","article-title":"Isolation and characterization of a hyaluronidase from the venom of Chinese red scorpion Buthus martensi","volume":"148","author":"Feng","year":"2008","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1074\/jbc.M205662200","article-title":"Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2","volume":"278","author":"Deshane","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3892\/etm.2012.548","article-title":"Scorpion venom component III inhibits cell proliferation by modulating NF-\u03baB activation in human leukemia cells","volume":"4","author":"Song","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Nosouhian, M., Rastegari, A.A., Shahanipour, K., Ahadi, A.M., and Sajjadieh, M.S. (2024). Anticancer potentiality of Hottentotta saulcyi scorpion curd venom against breast cancer: An in vitro and in vivo study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-75183-w"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"tfae174","DOI":"10.1093\/toxres\/tfae174","article-title":"Design and computational analysis of a novel Leptulipin-p28 fusion protein as a multitarget anticancer therapy in breast cancer","volume":"13","author":"Khalid","year":"2024","journal-title":"Toxicol. Res."},{"key":"ref_51","first-page":"27","article-title":"Design and construction of a chimeric peptide, MeICT\/IMe-AGAP, from two anti-cancer toxins of Iranian Mesobuthus eupeus scorpion","volume":"12","author":"Seifi","year":"2023","journal-title":"Mol. Biol. Res. Commun."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/9\/3181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:26:59Z","timestamp":1760030819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/9\/3181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,4]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["jcm14093181"],"URL":"https:\/\/doi.org\/10.3390\/jcm14093181","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,4]]}}}