{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T19:47:51Z","timestamp":1770580071409,"version":"3.49.0"},"reference-count":156,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,31]],"date-time":"2021-01-31T00:00:00Z","timestamp":1612051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04423\/2020 and UIDP\/04423\/2020"],"award-info":[{"award-number":["UIDB\/04423\/2020 and UIDP\/04423\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ICBAS - University of Porto","award":["Doctoral Program in Biomedical Sciences"],"award-info":[{"award-number":["Doctoral Program in Biomedical Sciences"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Seaweed bioactive compounds have shown anticancer activities in in vitro and in vivo studies. However, tests remain limited, with conflicting results, and effects in combination with anticancer drugs are even scarcer. Here, the cytotoxic effects of five seaweed compounds (astaxanthin, fucoidan, fucosterol, laminarin, and phloroglucinol) were tested alone and in combination with anticancer drugs (cisplatin\u2014Cis; and doxorubicin\u2014Dox), in breast cell lines (three breast cancer (BC) subtypes and one non-tumoral). The combinations revealed situations where seaweed compounds presented potentiation or inhibition of the drugs\u2019 cytotoxicity, without a specific pattern, varying according to the cell line, concentration used for the combination, and drug. Fucosterol was the most promising compound, since: (i) it alone had the highest cytotoxicity at low concentrations against the BC lines without affecting the non-tumoral line; and (ii) in combination (at non-cytotoxic concentration), it potentiated Dox cytotoxicity in the triple-negative BC cell line. Using a comparative approach, monolayer versus 3D cultures, further investigation assessed effects on cell viability and proliferation, morphology, and immunocytochemistry targets. The cytotoxic and antiproliferative effects in monolayer were not observed in 3D, corroborating that cells in 3D culture are more resistant to treatments, and reinforcing the use of more complex models for drug screening and a multi-approach that should include histological and ICC analysis.<\/jats:p>","DOI":"10.3390\/toxics9020024","type":"journal-article","created":{"date-parts":[[2021,1,31]],"date-time":"2021-01-31T21:31:56Z","timestamp":1612128716000},"page":"24","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Cytotoxicity of Seaweed Compounds, Alone or Combined to Reference Drugs, against Breast Cell Lines Cultured in 2D and 3D"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-5358","authenticated-orcid":false,"given":"Fernanda","family":"Malh\u00e3o","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U.Porto), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Center for Marine and Environmental Research (CIIMAR), University of Porto (U.Porto), Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"}]},{"given":"Alice","family":"Ramos","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U.Porto), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Center for Marine and Environmental Research (CIIMAR), University of Porto (U.Porto), Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3533-7343","authenticated-orcid":false,"given":"Ana","family":"Macedo","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U.Porto), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Center for Marine and Environmental Research (CIIMAR), University of Porto (U.Porto), Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9813-4389","authenticated-orcid":false,"given":"Eduardo","family":"Rocha","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U.Porto), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Center for Marine and Environmental Research (CIIMAR), University of Porto (U.Porto), Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40659-017-0140-9","article-title":"Awareness and current knowledge of breast cancer","volume":"50","author":"Akram","year":"2017","journal-title":"Biol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.cpet.2018.02.006","article-title":"Overview of breast cancer therapy","volume":"13","author":"Moo","year":"2018","journal-title":"PET Clin."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lin, Y., Zhang, W., Cao, H., Li, G., and Du, W. (2020). Classifying breast cancer subtypes using deep neural networks based on multi-omics data. Genes, 11.","DOI":"10.3390\/genes11080888"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.soc.2017.08.005","article-title":"Molecular subtypes and local-regional control of breast cancer","volume":"27","author":"Fragomeni","year":"2018","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1172\/JCI60534","article-title":"Heterogeneity in breast cancer","volume":"121","author":"Polyak","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5306\/wjco.v8.i2.120","article-title":"Targeted therapies in breast cancer: New challenges to fight against resistance","volume":"8","author":"Masoud","year":"2017","journal-title":"World J. Clin. Oncol."},{"key":"ref_8","first-page":"405","article-title":"Endocrine therapy for early breast cancer: Updated review","volume":"17","author":"Tremont","year":"2017","journal-title":"Ochsner J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41392-019-0069-2","article-title":"Targeted therapeutic options and future perspectives for HER2-positive breast cancer","volume":"4","author":"Wang","year":"2019","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12935-015-0221-1","article-title":"Resistance to cancer chemotherapy: Failure in drug response from ADME to P-gp","volume":"15","author":"Alfarouk","year":"2015","journal-title":"Cancer Cell Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1007\/s10549-020-05703-5","article-title":"Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients","volume":"182","author":"Cho","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/nar\/gkz337","article-title":"DrugComb: An integrative cancer drug combination data portal","volume":"47","author":"Zagidullin","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1016\/j.cell.2017.11.009","article-title":"Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy","volume":"171","author":"Palmer","year":"2017","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1186\/s12918-018-0546-1","article-title":"In silico drug combination discovery for personalized cancer therapy","volume":"12","author":"Jeon","year":"2018","journal-title":"BMC Syst. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"915375","DOI":"10.1155\/2012\/915375","article-title":"Combination drug delivery approaches in metastatic breast cancer","volume":"2012","author":"Lee","year":"2012","journal-title":"J. Drug Deliv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"192464","DOI":"10.1155\/2012\/192464","article-title":"The role of nutraceuticals in chemoprevention and chemotherapy and their clinical outcomes","volume":"2012","author":"Saldanha","year":"2012","journal-title":"J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"767136","DOI":"10.1155\/2015\/767136","article-title":"Overcome cancer cell drug resistance using natural products","volume":"2015","author":"Wang","year":"2015","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.taap.2017.06.007","article-title":"Antitumor effectiveness of a combined therapy with a new cucurbitacin B derivative and paclitaxel on a human lung cancer xenograft model","volume":"329","author":"Marostica","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","first-page":"214186","article-title":"Anticancer drugs from marine flora: An overview","volume":"2010","author":"Boopathy","year":"2010","journal-title":"J. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1021\/np200906s","article-title":"Natural products as sources of new drugs over the 30 years from 1981 to 2010","volume":"75","author":"Newman","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_21","first-page":"768323","article-title":"Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae","volume":"2014","author":"Moghadamtousi","year":"2014","journal-title":"Sci. World J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.phytol.2015.09.007","article-title":"Bioactive compounds from brown seaweeds: Phloroglucinol, fucoxanthin and fucoidan as promising therapeutic agents against breast cancer","volume":"14","author":"Rocha","year":"2015","journal-title":"Phytochem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.drudis.2017.10.019","article-title":"Anticancer activity of seaweeds","volume":"23","author":"Zepeda","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rocha, D.H.A., Seca, A.M.L., and Pinto, D.C.G.A. (2018). Seaweed secondary metabolites in vitro and in vivo anticancer activity. Mar. Drugs, 16.","DOI":"10.3390\/md16110410"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1007\/s10811-014-0245-2","article-title":"The potential of seaweed as a source of drugs for use in cancer chemotherapy","volume":"26","author":"Murphy","year":"2014","journal-title":"J. Appl. Phycol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437948","DOI":"10.1155\/2013\/437948","article-title":"Herbal medicine and acupuncture for breast cancer palliative care and adjuvant therapy","volume":"2013","author":"Liao","year":"2013","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4898","DOI":"10.3390\/md12094898","article-title":"Anticancer effects of different seaweeds on human colon and breast cancers","volume":"12","author":"Moussavou","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1017\/S0007114509993242","article-title":"A case\u2013control study on seaweed consumption and the risk of breast cancer","volume":"103","author":"Yang","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s10811-012-9931-0","article-title":"The consumption of seaweed as a protective factor in the etiology of breast cancer: Proof of principle","volume":"25","author":"Teas","year":"2013","journal-title":"J. Appl. Phycol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1080\/01635581.2013.757628","article-title":"Fucoidan inhibited 4T1 mouse breast cancer cell growth in vivo and in vitro via downregulation of Wnt\/beta-catenin signaling","volume":"65","author":"Xue","year":"2013","journal-title":"Nutr. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1111\/bph.14816","article-title":"Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence","volume":"177","author":"Lin","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lichota, A., and Gwozdzinski, K. (2018). Anticancer activity of natural compounds from plant and marine environment. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113533"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5493\/wjem.v2.i3.45","article-title":"Natural compounds as anticancer agents: Experimental evidence","volume":"2","author":"Wang","year":"2012","journal-title":"World J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.canlet.2012.05.012","article-title":"Green tea: An effective synergist with anticancer drugs for tertiary cancer prevention","volume":"324","author":"Fujiki","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kapadia, G.J., Rao, G.S., Ramachandran, C., Iida, A., Suzuki, N., and Tokuda, H. (2013). Synergistic cytotoxicity of red beetroot (Beta vulgaris L.) extract with doxorubicin in human pancreatic, breast and prostate cancer cell lines. J. Altern. Complement. Med., 10.","DOI":"10.1515\/jcim-2013-0007"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1080\/15287394.2017.1357297","article-title":"Anticancer effects of seaweed compounds fucoxanthin and phloroglucinol, alone and in combination with 5-fluorouracil in colon cells","volume":"80","author":"Abreu","year":"2017","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1080\/15287394.2019.1634378","article-title":"Cytotoxic activity of the seaweed compound fucosterol, alone and in combination with 5-fluorouracil, in colon cells using 2D and 3D culturing","volume":"82","author":"Ramos","year":"2019","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153280","DOI":"10.1016\/j.phymed.2020.153280","article-title":"The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes","volume":"77","author":"Eid","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1007\/s10517-007-0226-4","article-title":"Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide isolated from the Okhotsk Sea Fucus evanescens brown alga","volume":"143","author":"Alekseyenko","year":"2007","journal-title":"Exp. Biol. Med."},{"key":"ref_40","first-page":"641","article-title":"Phloroglucinol combined with parecoxib for cystospasm after transurethral resection of the prostate","volume":"22","author":"Cheng","year":"2016","journal-title":"Zhonghua Nan Ke Xue"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1186\/1471-2407-11-372","article-title":"Antioxidants and breast cancer risk- a population-based case-control study in Canada","volume":"11","author":"Pan","year":"2011","journal-title":"BMC Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1093\/ajcn\/nqy223","article-title":"Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy","volume":"109","author":"Jung","year":"2019","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1158\/1055-9965.EPI-10-1072","article-title":"Vitamin supplement use during breast cancer treatment and survival: A prospective cohort study","volume":"20","author":"Nechuta","year":"2011","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3389\/fbioe.2020.00322","article-title":"Cell culture based in vitro test systems for anticancer drug screening","volume":"8","author":"Kitaeva","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.3892\/or.2015.3767","article-title":"Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer","volume":"33","author":"Imamura","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1002\/jcp.25664","article-title":"Contributions of 3D cell cultures for cancer research","volume":"232","author":"Ravi","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.biotechadv.2016.11.002","article-title":"3D tumor spheroids: An overview on the tools and techniques used for their analysis","volume":"34","author":"Costa","year":"2016","journal-title":"Biotechnol. Adv."},{"key":"ref_48","first-page":"910","article-title":"2D and 3D cell cultures\u2014A comparison of different types of cancer cell cultures","volume":"14","author":"Kolenda","year":"2018","journal-title":"Arch. Med. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mikhail, A.S., Eetezadi, S., and Allen, C. (2013). Multicellular tumor spheroids for evaluation of cytotoxicity and tumor growth inhibitory effects of nanomedicines in vitro: A comparison of docetaxel-loaded block copolymer micelles and Taxotere\u00ae. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062630"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/adt.2014.573","article-title":"Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors","volume":"12","author":"Edmondson","year":"2014","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.drudis.2012.10.003","article-title":"Three-dimensional cell culture: The missing link in drug discovery","volume":"18","author":"Breslin","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/bcr2889","article-title":"Choosing the right cell line for breast cancer research","volume":"13","author":"Holliday","year":"2011","journal-title":"Breast Cancer Res. BCR"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1177\/117822341000400004","article-title":"The expression patterns of ER, PR, HER2, CK5\/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines","volume":"4","author":"Subik","year":"2010","journal-title":"Breast Cancer Basic Clin. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kim, S.K. (2015). Seaweed carotenoids for cancer therapeutics. Handbook of Anticancer Drugs from Marine Origin, Springer.","DOI":"10.1007\/978-3-319-07145-9"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1207\/S15327914NC3601_9","article-title":"Antitumor activity of astaxanthin and its mode of action","volume":"36","author":"Jyonouchi","year":"2000","journal-title":"Nutr. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"108364","DOI":"10.1016\/j.abb.2020.108364","article-title":"Nutraceutical characteristics of the brown seaweed carotenoid fucoxanthin","volume":"686","author":"Miyashita","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.3390\/molecules17033202","article-title":"Cancer chemoprevention by carotenoids","volume":"17","author":"Tanaka","year":"2012","journal-title":"Molecules"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1248\/bpb.34.839","article-title":"Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells","volume":"34","author":"Song","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.abb.2011.05.004","article-title":"Carotenoids inhibit proliferation and regulate expression of peroxisome proliferators-activated receptor gamma (PPAR\u03b3) in K562 cancer cells","volume":"512","author":"Zhang","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1016\/j.bbagen.2013.05.032","article-title":"Astaxanthin inhibits NF-\u03baB and Wnt\/\u03b2-catenin signaling pathways via inactivation of Erk\/MAPK and PI3K\/Akt to induce intrinsic apoptosis in a hamster model of oral cancer","volume":"1830","author":"Kavitha","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3109\/15376516.2012.717119","article-title":"Changes in cell ultrastructure and inhibition of JAK1\/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin","volume":"22","author":"Song","year":"2012","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"McCall, B., McPartland, C.K., Moore, R., Frank-Kamenetskii, A., and Booth, B.W. (2018). Effects of astaxanthin on the proliferation and migration of breast cancer cells in vitro. Antioxidants, 7.","DOI":"10.3390\/antiox7100135"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cbi.2011.05.006","article-title":"Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines","volume":"193","author":"Yasui","year":"2011","journal-title":"Chem. Biol. Interact."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Cunha, L., and Grenha, A. (2016). Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applications. Mar. Drugs, 14.","DOI":"10.3390\/md14030042"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1271\/bbb.59.563","article-title":"Antitumor active fucoidan from the brown seaweed, Umitoranoo (Sargassum thunbergii)","volume":"59","author":"Zhuang","year":"1995","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1093\/glycob\/cwm014","article-title":"A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds","volume":"17","author":"Cumashi","year":"2007","journal-title":"Glycobiology"},{"key":"ref_67","first-page":"6041","article-title":"Fucoidans stimulate immune reaction and suppress cancer growth","volume":"37","author":"Vetvicka","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.3892\/mmr.2015.3804","article-title":"Fucoidan inhibits the migration and proliferation of HT-29 human colon cancer cells via the phosphoinositide-3 kinase\/Akt\/mechanistic target of rapamycin pathways","volume":"12","author":"Han","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.toxrep.2019.06.005","article-title":"Anticancer effect of fucoidan on cell proliferation, cell cycle progression, genetic damage and apoptotic cell death in HepG2 cancer cells","volume":"6","author":"Arumugam","year":"2019","journal-title":"Toxicol. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40169-019-0234-9","article-title":"Clinical applications of fucoidan in translational medicine for adjuvant cancer therapy","volume":"8","author":"Hsu","year":"2019","journal-title":"Clin. Transl. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"8677","DOI":"10.1021\/jf9010406","article-title":"Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells","volume":"57","author":"Yamasaki","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Teruya, K., Eto, H., and Shirahata, S. (2011). Fucoidan extract induces apoptosis in MCF-7 cells via a mechanism involving the ROS-dependent JNK Activation and mitochondria-mediated pathways. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027441"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3390\/md11010081","article-title":"Fucoidan extract enhances the anti-cancer activity of chemotherapeutic agents in MDA-MB-231 and MCF-7 breast cancer cells","volume":"11","author":"Zhang","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1271\/bbb.120631","article-title":"Induction of apoptosis by low-molecular-weight fucoidan through calcium- and caspase-pependent mitochondrial pathways in MDA-MB-231 breast cancer cells","volume":"77","author":"Zhang","year":"2013","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1016\/j.carres.2011.09.034","article-title":"Sulfated polysaccharides from brown seaweeds Saccharina japonica and Undaria pinnatifida: Isolation, structural characteristics, and antitumor activity","volume":"346","author":"Vishchuk","year":"2011","journal-title":"Carbohydr. Res."},{"key":"ref_76","first-page":"2285","article-title":"In vitro effects of fucans on MDA-MB231 tumor cell adhesion and invasion","volume":"22","author":"Lindenmeyer","year":"2002","journal-title":"Anticancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"734","DOI":"10.3892\/ijmm.2012.1084","article-title":"Induction of apoptosis by laminarin, regulating the insulin-like growth factor-IR signaling pathways in HT-29 human colon cells","volume":"30","author":"Park","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"38554","DOI":"10.18632\/oncotarget.16170","article-title":"Laminarin promotes anti-cancer immunity by the maturation of dendritic cells","volume":"8","author":"Song","year":"2017","journal-title":"Oncotarget"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3892\/ijmm.2013.1409","article-title":"Induction of apoptosis and the regulation of ErbB signaling by laminarin in HT-29 human colon cancer cells","volume":"32","author":"Park","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.3892\/ol.2014.1952","article-title":"Laminarin-induced apoptosis in human colon cancer LoVo cells","volume":"7","author":"Ji","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"86693","DOI":"10.18632\/oncotarget.21411","article-title":"The \u03b2-glucan from Lentinus edodes suppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers","volume":"8","author":"Xu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s10811-016-0915-3","article-title":"In vitro anticancer activity of the laminarans from far-eastern brown seaweeds and their sulfated derivatives","volume":"29","author":"Malyarenko","year":"2017","journal-title":"J. Appl. Phycol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.chemphyslip.2017.03.010","article-title":"Effects of seaweed sterols fucosterol and desmosterol on lipid membranes","volume":"205","author":"Mouritsen","year":"2017","journal-title":"Chem. Phys. Lipids"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1002\/jsfa.7489","article-title":"Health benefit of fucosterol from marine algae: A review","volume":"96","author":"Abdul","year":"2016","journal-title":"J. Sci. Food Agric."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/B978-0-12-387669-0.00014-4","article-title":"Potential beneficial effects of marine algal sterols on human health","volume":"Volume 64","author":"Kim","year":"2011","journal-title":"Advances in Food and Nutrition Research"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4103\/0973-1296.93327","article-title":"Cytotoxicity of fucosterol containing fraction of marine algae against breast and colon carcinoma cell line","volume":"8","author":"Khanavi","year":"2012","journal-title":"Pharmacogn. Mag."},{"key":"ref_87","first-page":"3458","article-title":"Fucosterol exhibits selective antitumor anticancer activity against HeLa human cervical cell line by inducing mitochondrial mediated apoptosis, cell cycle migration inhibition and downregulation of m-TOR\/PI3K\/Akt signalling pathway","volume":"15","author":"Jiang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fbioe.2018.00185","article-title":"Cytotoxic activity of fatty acids from Antarctic macroalgae on the growth of human breast cancer cells","volume":"6","author":"Pacheco","year":"2018","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1016\/j.fct.2010.07.029","article-title":"Effect of phloroglucinol on oxidative stress and inflammation","volume":"48","author":"Kim","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.3892\/or.2014.3355","article-title":"Phloroglucinol induces apoptosis via apoptotic signaling pathways in HT-29 colon cancer cells","volume":"32","author":"Kang","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"46157","DOI":"10.1039\/C4RA06664B","article-title":"Unraveling the caspase-mediated mechanism for phloroglucinol-encapsulated starch biopolymer against the breast cancer cell line MDA-MB-231","volume":"4","author":"Kumar","year":"2014","journal-title":"RSC Adv."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.taap.2015.03.026","article-title":"Novel anticancer activity of phloroglucinol against breast cancer stem-like cells","volume":"286","author":"Kim","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fonc.2013.00134","article-title":"Cisplatin induces differentiation of breast cancer cells","volume":"3","author":"Prabhakaran","year":"2013","journal-title":"Front. Oncol"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s12935-019-0912-0","article-title":"Modulation of doxorubicin-induced expression of the multidrug resistance gene in breast cancer cells by diltiazem and protection against cardiotoxicity in experimental animals","volume":"19","author":"Osman","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s11101-019-09628-w","article-title":"The combinatory effects of natural products and chemotherapy drugs and their mechanisms in breast cancer treatment","volume":"19","author":"Zhang","year":"2020","journal-title":"Phytochem. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.phrs.2016.01.001","article-title":"Cisplatin resistance and opportunities for precision medicine","volume":"106","author":"Amable","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3727\/096504007783438358","article-title":"The proteomic analysis of cisplatin resistance in breast cancer cells","volume":"16","author":"Smith","year":"2007","journal-title":"Oncol. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0960-9776(01)80002-3","article-title":"Anthracyclines in breast cancer: Therapy and issues of toxicity","volume":"10","author":"Verrill","year":"2001","journal-title":"Breast"},{"key":"ref_99","first-page":"314","article-title":"Theoretical ground for adsorptive therapy of anthracyclines cardiotoxicity","volume":"34","author":"Shevchuk","year":"2012","journal-title":"Exp. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.tox.2010.03.012","article-title":"Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells","volume":"271","author":"Kahl","year":"2010","journal-title":"Toxicology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cmpb.2015.02.006","article-title":"A software suite for automatic image analysis of multicellular spheroids","volume":"119","author":"Piccinini","year":"2015","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.tibs.2018.08.004","article-title":"Ki-67: More hidden behind a \u2018classic proliferation marker\u2019","volume":"43","author":"Gil","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"7212","DOI":"10.1200\/JCO.2005.07.501","article-title":"Proliferation marker Ki-67 in early breast cancer","volume":"23","author":"Urruticoechea","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1369\/jhc.2008.952044","article-title":"Assessment of apoptosis by immunohistochemistry to active caspase-3, active caspase-7, or cleaved PARP in monolayer cells and spheroid and subcutaneous xenografts of human carcinoma","volume":"57","author":"Bressenot","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1089\/154065804322966315","article-title":"Use of multiple assay endpoints to investigate the effects of incubation time, dose of toxin, and plating density in cell-based cytotoxicity assays","volume":"2","author":"Riss","year":"2004","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_106","first-page":"65","article-title":"A simple sequentially rejective multiple test procedure","volume":"6","author":"Holm","year":"1979","journal-title":"Scand. J. Stat."},{"key":"ref_107","unstructured":"Gaetano, J. (2020, December 26). Holm-Bonferroni Sequential Correction: An Excel Calculator (1.3) [Microsoft Excel Workbook]. Available online: https:\/\/www.researchgate.net\/publication\/322568540_Holm-Bonferroni_sequential_correction_An_Excel_calculator_13."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3390\/biology3020345","article-title":"Advanced cell culture techniques for cancer drug discovery","volume":"3","author":"Lovitt","year":"2014","journal-title":"Biology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5261","DOI":"10.21873\/anticanres.13721","article-title":"Therapeutic application of diverse marine-derived natural products in cancer therapy","volume":"39","author":"Yun","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Rusdi, N.A., Kue, C.S., Yu, K.-X., Lau, B.F., Chung, L.Y., and Kiew, L.V. (2019). Assessment of potential anticancer activity of brown seaweed compounds using zebrafish phenotypic assay. Nat. Prod. Commun., 14.","DOI":"10.1177\/1934578X19857909"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.phymed.2018.04.062","article-title":"Drug resistance in glioblastoma and cytotoxicity of seaweed compounds, alone and in combination with anticancer drugs: A mini review","volume":"48","author":"Ferreira","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Varghese, E., Samuel, S.M., Abotaleb, M., Cheema, S., Mamtani, R., and B\u00fcsselberg, D. (2018). The \u201cYin and Yang\u201d of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers, 10.","DOI":"10.3390\/cancers10100346"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yrtph.2016.01.004","article-title":"Assessing natural product\u2013drug interactions: An end-to-end safety framework","volume":"76","author":"Roe","year":"2016","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"D\u2019Andrea, G.M. (2005). Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J. Clin., 55.","DOI":"10.3322\/canjclin.55.5.319"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.1349-7006.2001.tb01119.x","article-title":"Seaweed prevents breast cancer?","volume":"92","author":"Funahashi","year":"2001","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3892\/ijo.2016.3558","article-title":"Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines","volume":"49","author":"Calaf","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/sj.bjc.6600859","article-title":"BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells","volume":"88","author":"Tassone","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"12698","DOI":"10.1021\/acsomega.9b04369","article-title":"Identifying the responses from the estrogen receptor-expressed MCF7 cells treated in anticancer drugs of different modes of action using live-cell FTIR spectroscopy","volume":"5","author":"Altharawi","year":"2020","journal-title":"ACS Omega"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"13012","DOI":"10.1038\/s41598-019-49671-3","article-title":"3D cell culture stimulates the secretion of in vivo like extracellular vesicles","volume":"9","author":"Thippabhotla","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Karimian, A., Bahadori, M.H., Moghaddam, A.H., and Mohammadrezaei, F.M. (2017). Effect of astaxanthin on cell viability in T-47D and MDA-MB-231 breast cancer cell lines. Multidiscip. Cancer Investig., 1.","DOI":"10.21859\/mci-supp-71"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Franceschelli, S., Pesce, M., Ferrone, A., De Lutiis, M.A., Patruno, A., Grilli, A., Felaco, M., and Speranza, L. (2014). Astaxanthin treatment confers protection against oxidative stress in U937 cells stimulated with lipopolysaccharide reducing O2\u2212 production. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088359"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Yilmaz, Y., Tumkaya, L., Mercantepe, T., and Akyildiz, K. (2020). Protective effect of astaxanthin against cisplatin-induced gastrointestinal toxicity in rats. Eur. Surg.","DOI":"10.1007\/s10353-020-00643-2"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"K\u0131nal, M.E., Tatl\u0131p\u0131nar, A., Uzun, S., Keskin, S., Tekdemir, E., \u00d6zbeyli, D., and Akak\u0131n, D. (2019). Investigation of astaxanthin effect on cisplatin ototoxicity in rats by using otoacoustic emission, total antioxidant capacity, and histopathological methods. Ear Nose Throat J.","DOI":"10.1177\/0145561319866826"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1080\/15569527.2018.1518330","article-title":"The protective effects of astaxanthin against cisplatin-induced retinal toxicity","volume":"38","author":"Tumkaya","year":"2019","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s11596-013-1186-8","article-title":"Fucoidan induces G1 phase arrest and apoptosis through caspases-dependent pathway and ROS induction in human breast cancer MCF-7 cells","volume":"33","author":"Banafa","year":"2013","journal-title":"J. Huazhong Univ. Sci. Technolog. Med. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"748","DOI":"10.2174\/1389201018666171115115112","article-title":"Effects of fucoidan and chemotherapeutic agent combinations on malignant and non-malignant breast cell lines","volume":"18","author":"Abudabbus","year":"2017","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"110534","DOI":"10.1016\/j.biopha.2020.110534","article-title":"Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2\/STAT3-mediated apoptosis and autophagy","volume":"130","author":"Zhang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Reyes, M.E., Riquelme, I., Salvo, T., Zanella, L., Letelier, P., and Brebi, P. (2020). Brown seaweed fucoidan in cancer: Implications in metastasis and drug resistance. Mar. Drugs, 18.","DOI":"10.3390\/md18050232"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10529-005-6177-9","article-title":"Anti-apoptotic activity of laminarin polysaccharides and their enzymatically hydrolyzed oligosaccharides from Laminaria japonica","volume":"28","author":"Kim","year":"2006","journal-title":"Biotechnol. Lett."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"117007","DOI":"10.1016\/j.carbpol.2020.117007","article-title":"Aminated laminaran from brown alga Saccharina cichorioides: Synthesis, structure, anticancer, and radiosensitizing potential in vitro","volume":"250","author":"Malyarenko","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"ref_131","first-page":"1","article-title":"Protective effects of laminarin on cisplatin-induced ototoxicity in HEIOC1 auditory cells","volume":"6","author":"Han","year":"2016","journal-title":"J. Nutr. Food Sci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/cas.12562","article-title":"Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition","volume":"106","author":"Kim","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"8782","DOI":"10.1021\/jf900935n","article-title":"Phloroglucinols inhibit chemical mediators and xanthine oxidase, and protect cisplatin-induced cell death by reducing reactive oxygen species in normal human urothelial and bladder cancer cells","volume":"57","author":"Lin","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.ygyno.2014.11.015","article-title":"Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity","volume":"136","author":"Yang","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1089\/jmf.2017.3919","article-title":"Cardioprotective effects of a phlorotannin extract against doxorubicin-induced cardiotoxicity in a rat model","volume":"20","author":"Ahn","year":"2017","journal-title":"J. Med. Food"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.fitote.2017.09.020","article-title":"New phloroglucinol derivatives from the whole plant of Hypericum uralum","volume":"123","author":"Li","year":"2017","journal-title":"Fitoterapia"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Lu, J., Shi, K.K., Chen, S., Wang, J., Hassouna, A., White, L.N., Merien, F., Xie, M., Kong, Q., and Li, J. (2018). Fucoidan extracted from the New Zealand Undaria pinnatifida-physicochemical comparison against five other fucoidans: Unique low molecular weight fraction bioactivity in breast cancer cell lines. Mar. Drugs, 16.","DOI":"10.3390\/md16120461"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/jphp.12241","article-title":"Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes","volume":"66","author":"Jung","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"152809","DOI":"10.1016\/j.phymed.2018.12.032","article-title":"Fucosterol exerts antiproliferative effects on human lung cancer cells by inducing apoptosis, cell cycle arrest and targeting of Raf\/MEK\/ERK signalling pathway","volume":"61","author":"Mao","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1111\/jphp.12404","article-title":"Protective effect of fucosterol isolated from the edible brown algae, Ecklonia stolonifera and Eisenia bicyclis, on tert-butyl hydroperoxide- and tacrine-induced HepG2 cell injury","volume":"67","author":"Choi","year":"2015","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Bae, H., Lee, J.-Y., Song, G., and Lim, W. (2020). Fucosterol suppresses the progression of human ovarian cancer by inducing mitochondrial dysfunction and endoplasmic reticulum stress. Mar. Drugs, 18.","DOI":"10.3390\/md18050261"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00404-015-3859-y","article-title":"An overview of triple-negative breast cancer","volume":"293","author":"Kumar","year":"2016","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_143","first-page":"2029","article-title":"Breast cancer intrinsic subtype classification, clinical use and future trends","volume":"10","author":"Dai","year":"2015","journal-title":"Am. J. Cancer"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.soc.2017.08.004","article-title":"Triple-negative breast cancer: Who should receive neoadjuvant chemotherapy?","volume":"27","author":"Chaudhary","year":"2018","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Cocco, S., Piezzo, M., Calabrese, A., Cianniello, D., Caputo, R., Lauro, V.D., Fusco, G., Gioia, G.D., Licenziato, M., and Laurentiis, M.D. (2020). Biomarkers in triple-negative breast cancer: State-of-the-art and future perspectives. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134579"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"102855","DOI":"10.1016\/j.critrevonc.2019.102855","article-title":"Triple negative breast cancer: A thorough review of biomarkers","volume":"145","author":"Izetti","year":"2020","journal-title":"Crit Rev. Oncol. Hematol."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Nedeljkovi\u0107, M., and Damjanovi\u0107, A. (2019). Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells, 8.","DOI":"10.3390\/cells8090957"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ddtec.2017.03.002","article-title":"The production of 3D tumor spheroids for cancer drug discovery","volume":"23","author":"Sant","year":"2017","journal-title":"Drug Discov. Today Technol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrc1893","article-title":"Drug penetration in solid tumours","volume":"6","author":"Minchinton","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.3109\/13880209.2014.886273","article-title":"Cytotoxic and antiproliferative constituents from Dictyota ciliolata, Padina sanctae-crucis and Turbinaria tricostata","volume":"52","author":"Robledo","year":"2014","journal-title":"Pharm. Biol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"110264","DOI":"10.1016\/j.msec.2019.110264","article-title":"Comparison of 2D and 3D cell culture models for cell growth, gene expression and drug resistance","volume":"107","author":"Fontoura","year":"2020","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fphar.2018.00006","article-title":"Three-Dimensional in vitro cell culture models in drug discovery and drug repositioning","volume":"9","author":"Langhans","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Lovitt, C.J., Shelper, T.B., and Avery, V.M. (2018). Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3953-6"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"e1800268","DOI":"10.1002\/biot.201800268","article-title":"Establishment of 2D cell cultures derived from 3D MCF-7 spheroids displaying a doxorubicin resistant profile","volume":"14","author":"Nunes","year":"2019","journal-title":"Biotechnol. J."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1152\/nips.01519.2004","article-title":"Morphological features of cell death","volume":"19","author":"Ziegler","year":"2004","journal-title":"Physiology"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S0008-6363(99)00384-3","article-title":"Morphologic and biochemical hallmarks of apoptosis","volume":"45","author":"Saraste","year":"2000","journal-title":"Cardiovasc. 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