{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:30:29Z","timestamp":1763566229218,"version":"3.45.0"},"reference-count":61,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia I.P.","award":["UID\/50017\/2025","LA\/P\/0094\/2020"],"award-info":[{"award-number":["UID\/50017\/2025","LA\/P\/0094\/2020"]}]},{"name":"CICECO\u2014Aveiro Institute of Materials","award":["UID\/50011\/2025","LA\/P\/0006\/2020"],"award-info":[{"award-number":["UID\/50011\/2025","LA\/P\/0006\/2020"]}]},{"name":"Rajagiri College of Social Sciences (Autonomous), Kerala, India","award":["RCSS\/IQAC\/BB-S59\/2025\/159"],"award-info":[{"award-number":["RCSS\/IQAC\/BB-S59\/2025\/159"]}]},{"DOI":"10.13039\/100007689","name":"University of Aveiro","doi-asserted-by":"publisher","award":["BI\/REIT\/11869\/2024"],"award-info":[{"award-number":["BI\/REIT\/11869\/2024"]}],"id":[{"id":"10.13039\/100007689","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Melanoma, in advanced stages, is the most invasive type of skin cancer, with currently available treatments showing limited efficiency. The number of melanoma cancer cases is expected to increase in the coming years, emphasizing the need for more efficient therapeutic strategies. The present study aimed to evaluate the potential of \u03b2-blockers, commonly used to treat cardiac conditions, to be repurposed for the treatment of melanoma. The effects of non-selective \u03b2-blockers (carvedilol and propranolol), \u03b21 selective blockers (atenolol and metoprolol) and antineoplastics drugs (cisplatin and 5-fluorouracil) on the A375 melanoma cell line were studied, individually and in combined exposures, by assessing cell viability over a 72 h period. The 72 h half-maximal inhibitory concentrations (IC50s) determined for A375 cells allow the ranking of toxicity as: cisplatin (2.46 (1.87\u20133.38) \u03bcM) &gt; 5-fluorouracil (4.77 (4.48\u20135.07) \u03bcM) &gt; carvedilol (16.91 (15.47\u201318.99) \u03bcM) &gt; propranolol (58.03 (57.08\u201359.11) \u03bcM) &gt; atenolol and metoprolol (\u03b21 selective blockers that exhibited no significant effect on the cell\u2019s viability). The effects of combined exposures were also studied. Metoprolol and carvedilol exhibited synergistic interactions with cisplatin at specific concentrations. Overall, the data highlight the concentration-dependent nature of mixture effects and support the potential application of \u03b2-blockers melanoma treatment.<\/jats:p>","DOI":"10.3390\/toxics13110981","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T17:33:21Z","timestamp":1763141601000},"page":"981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beta-Blockers as Potential Adjuvants in Melanoma Treatment"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1753-4407","authenticated-orcid":false,"given":"Laura","family":"Rama","sequence":"first","affiliation":[{"name":"Centre for Environmental and Marine Studies (CESAM), Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CICECO-Aveiro Institute of Materials, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5734-4021","authenticated-orcid":false,"given":"M\u00f3nica","family":"Almeida","sequence":"additional","affiliation":[{"name":"Centre for Environmental and Marine Studies (CESAM), Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Jiya","family":"Jose","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Rajagiri College of Social Sciences, Kochi 682039, Kerala, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-7869","authenticated-orcid":false,"given":"Maria de Lourdes","family":"Pereira","sequence":"additional","affiliation":[{"name":"CICECO-Aveiro Institute of Materials, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-7718","authenticated-orcid":false,"given":"Miguel","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centre for Environmental and Marine Studies (CESAM), Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","unstructured":"Ferlay, J., Ervik, M., Lam, F., Laversanne, M., Colombet, M., Mery, L., Pi\u00f1eros, M., Znaor, A., Soerjomataram, I., and Bray, F. (2024). Global Cancer Observatory: Cancer Today, International Agency for Research on Cancer. Available online: https:\/\/gco.iarc.who.int\/today."},{"key":"ref_2","unstructured":"SEER*Explorer: An Interactive Website for SEER Cancer Statistics (2023, March 31). Surveillance Research Program, National Cancer Institute, Available online: https:\/\/seer.cancer.gov\/explorer\/."},{"key":"ref_3","unstructured":"Ferlay, J., Laversanne, M., Ervik, M., Lam, F., Colombet, M., Mery, L., Pi\u00f1eros, M., Znaor, A., Soerjomataram, I., and Bray, F. (2024). Global Cancer Observatory: Cancer Tomorrow (version 1.1), International Agency for Research on Cancer. Available online: https:\/\/gco.iarc.who.int\/tomorrow."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1158\/1055-9965.EPI-09-1249","article-title":"Indoor tanning and risk of melanoma: A case-control study in a highly exposed population","volume":"19","author":"Lazovich","year":"2010","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Saginala, K., Barsouk, A., Aluru, J.S., Rawla, P., and Barsouk, A. (2021). Epidemiology of Melanoma. Med. Sci., 9.","DOI":"10.3390\/medsci9040063"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1002\/cncr.31345","article-title":"Melanoma: What do all the mutations mean?","volume":"124","author":"Davis","year":"2018","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Natarelli, N., Aleman, S.J., Mark, I.M., Tran, J.T., Kwak, S., Botto, E., Aflatooni, S., Diaz, M.J., and Lipner, S.R. (2024). A Review of Current and Pipeline Drugs for Treatment of Melanoma. Pharmaceuticals, 17.","DOI":"10.3390\/ph17020214"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s11912-023-01385-6","article-title":"Chemotherapy in Cutaneous Melanoma: Is There Still a Role?","volume":"25","author":"Pham","year":"2023","journal-title":"Curr. Oncol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Eddy, K., and Chen, S. (2020). Overcoming Immune Evasion in Melanoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21238984"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lopes, J., Rodrigues, C.M.P., Gaspar, M.M., and Reis, C.P. (2022). Melanoma Management: From Epidemiology to Treatment and Latest Advances. Cancers, 14.","DOI":"10.3390\/cancers14194652"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1134\/S1068162023020139","article-title":"Drug Repurposing: An Effective Tool in Modern Drug Discovery","volume":"49","author":"Kulkarni","year":"2023","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xia, Y., Sun, M., Huang, H., and Jin, W.L. (2024). Drug repurposing for cancer therapy. Signal Transduct. Target. Ther., 9.","DOI":"10.1038\/s41392-024-01808-1"},{"key":"ref_13","unstructured":"Farzam, K., and Jan, A. (2024, June 26). Beta Blockers, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK532906\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.recesp.2019.02.023","article-title":"Beta-blockers: Historical Perspective and Mechanisms of Action","volume":"72","author":"Oliver","year":"2019","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Peixoto, R., Pereira, M.L., and Oliveira, M. (2020). Beta-Blockers and Cancer: Where Are We?. Pharmaceuticals, 13.","DOI":"10.3390\/ph13060105"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Massalee, R., and Cao, X. (2024). Repurposing beta-blockers for combinatory cancer treatment: Effects on conventional and immune therapies. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1325050"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, B., Ban, F., Li, Y., Shi, Q., Guo, S., Yi, X., Wang, H., Gao, T., Li, C., and Zhu, G. (2025). Exploiting mitochondrial dysfunction to overcome BRAF inhibitor resistance in advanced melanoma: The role of disulfiram as a copper ionophore. Cell Death Dis., 16.","DOI":"10.1038\/s41419-025-07766-y"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Calvani, M., Bruno, G., Dabraio, A., Subbiani, A., Bianchini, F., Fontani, F., Casazza, G., Vignoli, M., De Logu, F., and Frenos, S. (2020). \u03b23-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041420"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/1078-0432.CCR-11-0641","article-title":"Molecular pathways: Beta-adrenergic signaling in cancer","volume":"18","author":"Cole","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1096\/fba.2021-00097","article-title":"\u03b2-Adrenergic signaling in skin cancer","volume":"4","author":"Ali","year":"2022","journal-title":"FASEB BioAdv."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Sharma, A.E., Chan, S., Komorowski, A.S., Cao, X., Gao, Y., Kshatri, K., Desai, K., Kuksis, M., Rosen, M., and Sachdeva, A. (2025). The Impact of Beta Blockers on Survival in Cancer Patients: A Systematic Review and Meta-Analysis. Cancers, 17.","DOI":"10.3390\/cancers17081357"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"O\u2019Logbon, J., Tarantola, L., Williams, N.R., Mehta, S., Ahmed, A., and Davies, E.A. (2025). Does propranolol have a role in cancer treatment? A systematic review of the epidemiological and clinical trial literature on beta-blockers. J. Cancer Res. Clin. Oncol., 151.","DOI":"10.1007\/s00432-025-06262-2"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, F., Wang, Y., Liu, F., Li, Y., Liu, X., Ren, X., and Yuan, X. (2025). Impact of beta blockers on cancer neuroimmunology: A systematic review and meta-analysis of survival outcomes and immune modulation. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1635331"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fateeva, A., Eddy, K., and Chen, S. (2024). Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance. Cancers, 16.","DOI":"10.3390\/cancers16081571"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Muller, N.M., Tan, S.X., Vipulaguna, N., Zhou, C., Hughes, M.C.B., Soyer, H.P., von Schuckmann, L., and Khosrotehrani, K. (2025). Beta-blockers and cutaneous melanoma outcomes: A systematic review and random-effects meta-analysis. Pigment Cell Melanoma Res., 38.","DOI":"10.1111\/pcmr.13225"},{"key":"ref_26","unstructured":"Markossian, S., Grossman, A., Brimacombe, K., Arkin, M., Auld, D., Austin, C., Baell, J., Brimacombe, K., Chung, T.D.Y., and Coussens, N.P. (2024, June 26). Cell Viability Assays, Assay Guidance Manual, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK144065\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: An interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.jsps.2023.05.020","article-title":"In vitro and in silico study on the effect of carvedilol and sorafenib alone and in combination on the growth and inflammatory response of melanoma cells","volume":"31","author":"Wawszczyk","year":"2023","journal-title":"Saudi Pharm. J."},{"key":"ref_29","first-page":"387","article-title":"Inhibition of proliferation on some neoplastic cell lines-act of carvedilol and captopril","volume":"24","author":"Stanojkovic","year":"2005","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_30","first-page":"998","article-title":"Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP\/PKA and PKC\u03b4 signaling pathway","volume":"10","author":"Dezong","year":"2014","journal-title":"J. Cancer Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ejca.2021.01.029","article-title":"Carvedilol blocks neural regulation of breast cancer progression in vivo and is associated with reduced breast cancer mortality in patients","volume":"147","author":"Gillis","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Farhoumand, L.S., Fiorentzis, M., Kraemer, M.M., Sak, A., Stuschke, M., Rassaf, T., Hendgen-Cotta, U., Bechrakis, N.E., and Berchner-Pfannschmidt, U. (2022). The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation. Cancers, 14.","DOI":"10.3390\/cancers14133097"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijcard.2015.02.015","article-title":"Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study","volume":"184","author":"Lin","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.18632\/oncotarget.14119","article-title":"Use of non-selective \u03b2-blockers is associated with decreased tumor proliferative indices in early stage breast cancer","volume":"8","author":"Montoya","year":"2017","journal-title":"Oncotarget"},{"key":"ref_35","first-page":"5213","article-title":"Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells","volume":"17","author":"Wang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Broh\u00e9e, L., Peulen, O., Nusgens, B., Castronovo, V., Thiry, M., Colige, A.C., and Deroanne, C.F. (2018). Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25340-9"},{"key":"ref_37","first-page":"292","article-title":"Anti-proliferative effects of beta-blocker propranolol on human lung cancer and noncancer cells","volume":"124","author":"Terzi","year":"2023","journal-title":"Bratisl. Med. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s10120-021-01184-7","article-title":"Propranolol suppresses gastric cancer cell growth by regulating proliferation and apoptosis","volume":"24","author":"Koh","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68314","DOI":"10.18632\/oncotarget.11599","article-title":"Propranolol induced G0\/G1\/S phase arrest and apoptosis in melanoma cells via AKT\/MAPK pathway","volume":"7","author":"Zhou","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/jid.2014.373","article-title":"Inhibition of human melanoma growth by a non-cardioselective \u03b2-blocker","volume":"135","author":"Wrobel","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.3892\/or.2015.3874","article-title":"Antiproliferative effects of \u03b2-blockers on human colorectal cancer cells","volume":"33","author":"Coelho","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Talarico, G., Orecchioni, S., Dallaglio, K., Reggiani, F., Mancuso, P., Calleri, A., Gregato, G., Labanca, V., Rossi, T., and Noonan, D.M. (2016). Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. Sci. Rep., 6.","DOI":"10.1038\/srep18673"},{"key":"ref_43","first-page":"124","article-title":"Cytotoxicity of Metoprolol on Leukemic Cells in Vitro","volume":"10","author":"Hajatbeigi","year":"2018","journal-title":"IJBC"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"He, D., Hu, J., Li, Y., and Zeng, X. (2022). Preventive use of beta-blockers for anthracycline-induced cardiotoxicity: A network meta-analysis. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.968534"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ma, Y., Bai, F., Qin, F., Li, J., Liu, N., Li, D., Li, T., Xie, H., Liu, D., and Zhou, S. (2019). Beta-blockers for the primary prevention of anthracycline-induced cardiotoxicity: A meta-analysis of randomized controlled trials. BMC Pharmacol. Toxicol., 20.","DOI":"10.1186\/s40360-019-0298-6"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/labinvest.2012.175","article-title":"\u03b2-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines","volume":"93","author":"Moretti","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Weng, C.H., Wu, C.S., Wu, J.C., Kung, M.L., Wu, M.H., and Tai, M.H. (2020). Cisplatin-Induced Giant Cells Formation Is Involved in Chemoresistance of Melanoma Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217892"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.jsps.2014.08.004","article-title":"Evaluation of anti-metastatic potential of Cisplatin polymeric nanocarriers on B16F10 melanoma cells","volume":"23","author":"Shrikhande","year":"2015","journal-title":"Saudi Pharm. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1248\/bpb.b18-00707","article-title":"Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer","volume":"42","author":"Lim","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.7150\/jca.20196","article-title":"Curcumin Enhances the Anticancer Effect Of 5-fluorouracil against Gastric Cancer through Down-Regulation of COX-2 and NF- \u03baB Signaling Pathways","volume":"8","author":"Yang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Majounie, E., Wee, K., Williamson, L.M., Jones, M.R., Pleasance, E., Lim, H.J., Ho, C., Renouf, D.J., Yip, S., and Jones, S.J.M. (2020). Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant. Mol. Case Stud., 6.","DOI":"10.1101\/mcs.a004713"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/jso.2930380409","article-title":"A role for topical 5-fluorouracil therapy in melanoma","volume":"38","author":"Ryan","year":"1988","journal-title":"J. Surg. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Focaccetti, C., Bruno, A., Magnani, E., Bartolini, D., Principi, E., Dallaglio, K., Bucci, E.O., Finzi, G., Sessa, F., and Noonan, D.M. (2015). Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0115686"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chaudhary, K.R., Yan, S.X., Heilbroner, S.P., Sonett, J.R., Stoopler, M.B., Shu, C., Halmos, B., Wang, T.J.C., Hei, T.K., and Cheng, S.K. (2019). Effects of \u03b2-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050575"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"797","DOI":"10.18632\/oncotarget.343","article-title":"Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: Implication in breast cancer treatment","volume":"2","author":"Pasquier","year":"2011","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1080\/15287394.2012.696512","article-title":"Carvedilol protects against apoptotic cell death induced by cisplatin in renal tubular epithelial cells","volume":"75","author":"Gobe","year":"2012","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1021\/acsptsci.4c00596","article-title":"In Vivo and In Vitro Pharmacokinetic Studies of a Dual Topoisomerase I\/II Inhibitor","volume":"8","author":"Hildebrandt","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Archer, M., Dogra, N., Dovey, Z., Ganta, T., Jang, H.-S., Khusid, J.A., Lantz, A., Mihalopoulos, M., Stockert, J.A., and Zahalka, A. (2021). Role of \u03b1- and \u03b2-adrenergic signaling in phenotypic targeting: Significance in benign and malignant urologic disease. Cell Commun. Signal, 19.","DOI":"10.1186\/s12964-021-00755-6"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Lin, Y., Liu, Y., Gao, Z., Jing, D., Bi, R., Cui, X., Cao, Q., Zhao, Q., Gao, R., and Su, Y. (2023). Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer. Eur. J. Pharmacol., 949.","DOI":"10.1016\/j.ejphar.2023.175718"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Carnet Le Provost, K., Kepp, O., Kroemer, G., and Bezu, L. (2023). Trial watch: Beta-blockers in cancer therapy. Oncoimmunology, 12.","DOI":"10.1080\/2162402X.2023.2284486"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1111\/bph.14552","article-title":"\u03b2-Adrenoceptors as drug targets in melanoma: Novel preclinical evidence for a role of \u03b23-adrenoceptors","volume":"176","author":"Calvani","year":"2019","journal-title":"Br. J. Pharmacol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/11\/981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:27:45Z","timestamp":1763566065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/11\/981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":61,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["toxics13110981"],"URL":"https:\/\/doi.org\/10.3390\/toxics13110981","relation":{},"ISSN":["2305-6304"],"issn-type":[{"type":"electronic","value":"2305-6304"}],"subject":[],"published":{"date-parts":[[2025,11,14]]}}}