{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:00:04Z","timestamp":1788267604274,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Center","award":["N\/NZ5\/02634"],"award-info":[{"award-number":["N\/NZ5\/02634"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Combination therapy is based on the beneficial effects of pharmacodynamic interaction (synergistic or additive) between combined drugs or substances. A considerable group of candidates for combined treatments are natural compounds (e.g., isothiocyanates) and their analogs, which are tested in combination with anticancer drugs. We tested the anticancer effect of the combined treatment of isothiocyanate 2-oxohexyl isothiocyanate and 5-fluorouracil in colon and prostate cancer cell lines. The type of interaction was described using the Chou-Talalay method. The cytostatic and cytotoxic activities of the most promising combined treatments were investigated. In conclusion, we showed that combined treatment with 5-fluorouracil and 2-oxohexyl isothiocyanate acted synergistically in colon cancer. This activity is dependent on the cytostatic properties of the tested compounds and leads to the intensification of their individual cytotoxic activity. The apoptotic process is considered to be the main mechanism of cytotoxicity in this combined treatment.<\/jats:p>","DOI":"10.3390\/molecules26103019","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T21:49:21Z","timestamp":1621460961000},"page":"3019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Synergistic Interaction between 5-FU and an Analog of Sulforaphane\u20142-Oxohexyl Isothiocyanate\u2014In an In Vitro Colon Cancer Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1209-9477","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Milczarek","sequence":"first","affiliation":[{"name":"Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 30\/34 Che\u0142mska St., 00-725 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-2682","authenticated-orcid":false,"given":"Anna","family":"Pogorzelska","sequence":"additional","affiliation":[{"name":"Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 30\/34 Che\u0142mska St., 00-725 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2731-9535","authenticated-orcid":false,"given":"Katarzyna","family":"Wiktorska","sequence":"additional","affiliation":[{"name":"Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 30\/34 Che\u0142mska St., 00-725 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"ref_1","first-page":"872","article-title":"Oral versus intravenous fluoropyrimidines for colorectal cancer","volume":"27","author":"Chionh","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yang, Y., Ma, L., Xu, Y., Liu, Y., Li, W., Cai, J., and Zhang, Y. (2020). Enalapril overcomes chemoresistance and potentiates antitumor efficacy of 5-FU in colorectal cancer by suppressing proliferation, angiogenesis, and NF-\u03baB\/STAT3-regulated proteins. Cell Death Dis., 11.","DOI":"10.1038\/s41419-020-2675-x"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1200\/JCO.2004.03.104","article-title":"Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: An updated meta-analysis","volume":"22","author":"Thirion","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4251\/wjgo.v6.i6.177","article-title":"Current Status of Pharmacological Treatment of Colorectal Cancer","volume":"6","author":"Akhtar","year":"2014","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clcc.2014.11.002","article-title":"A review of the evolution of systemic chemotherapy in the management of colorectal cancer","volume":"14","author":"Gustavsson","year":"2015","journal-title":"Clin. Colorectal Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38022","DOI":"10.18632\/oncotarget.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Mokhtari","year":"2017","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/nrc1887","article-title":"Drug interactions in cancer therapy","volume":"6","author":"Scripture","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paciello, F., Fetoni, A.R., Mezzogori, D., Rolesi, R., Di Pino, A., Paludetti, G., Grassi, C., and Troiani, D. (2020). The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-57965-0"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bose, C., Awasthi, S., Sharma, R., Bene\u0161, H., Hauer-Jensen, M., Boerma, M., and Singh, S.P. (2018). Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193918"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/ijc.23097","article-title":"Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R","volume":"122","author":"Patel","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6702","DOI":"10.1038\/sj.onc.1207630","article-title":"Sensitization for anticancer drug-induced apoptosis by the chemopreventive agent resveratrol","volume":"23","author":"Fulda","year":"2004","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"594","DOI":"10.3892\/or.2016.5246","article-title":"Restoration of the tumor-suppressor function to mutant p53 by Ganoderma lucidum polysaccharides in colorectal cancer cells","volume":"37","author":"Jiang","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.bbrc.2005.04.143","article-title":"Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways","volume":"332","author":"Hwang","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.canlet.2004.06.019","article-title":"Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts","volume":"215","author":"Carnesecchi","year":"2004","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1111\/j.1742-7843.2007.00115.x","article-title":"Effect of betulinic acid on anticancer drug-resistant colon cancer cells","volume":"101","author":"Jung","year":"2007","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00280-015-2749-0","article-title":"Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells","volume":"76","author":"Yang","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"799","DOI":"10.3390\/nu7020799","article-title":"Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer","volume":"7","author":"Wang","year":"2015","journal-title":"Nutrients"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/01635581.2015.989374","article-title":"Phellinus linteus extract induces autophagy and synergizes with 5-fluorouracil to inhibit breast cancer cell growth","volume":"67","author":"Lee","year":"2015","journal-title":"Nutr. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Milczarek, M., Wiktorska, K., Mielczarek, L., Koronkiewicz, M., D\u0105browska, A., Lubelska, K., Matosiuk, D., and Chilmonczyk, Z. (2018). Autophagic cell death and premature senescence: New mechanism of 5-fluorouracil and sulforaphane synergistic anticancer effect in MDA-MB-231 triple negative breast cancer cell line. Food Chem. Toxicol., 111.","DOI":"10.1016\/j.fct.2017.10.056"},{"key":"ref_20","first-page":"799","article-title":"Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells","volume":"10","author":"Alnuqaydan","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dey, D.K., Chang, S.N., Vadlamudi, Y., Park, J.G., and Kang, S.C. (2020). Synergistic therapy with tangeretin and 5-fluorouracil accelerates the ROS\/JNK mediated apoptotic pathway in human colorectal cancer cell. Food Chem. Toxicol., 143.","DOI":"10.1016\/j.fct.2020.111529"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Milczarek, M., Mielczarek, L., Lubelska, K., D\u0105browska, A., Chilmonczyk, Z., Matosiuk, D., and Wiktorska, K. (2018). In Vitro Evaluation of Sulforaphane and a Natural Analog as Potent Inducers of 5-Fluorouracil Anticancer Activity. Molecules, 23.","DOI":"10.3390\/molecules23113040"},{"key":"ref_23","first-page":"659","article-title":"Inhibition of cell cycle and induction of apoptosis by sulforaphane in cell lines carrying various inherited BRCA1 mutations","volume":"13","author":"Misiewicz","year":"2005","journal-title":"Oncol. Rep."},{"key":"ref_24","first-page":"2045","article-title":"Sulforaphane and 2-oxohexyl isothiocyanate induce cell growth arrest and apoptosis in L-1210 leukemia and ME-18 melanoma cells","volume":"10","author":"Misiewicz","year":"2003","journal-title":"Oncol. Rep."},{"key":"ref_25","first-page":"331","article-title":"Combination treatment with 5-fluorouracil and isothiocyanates shows an antagonistic effect in Chinese hamster fibroblast cells line-V79","volume":"68","author":"Milczarek","year":"2011","journal-title":"Acta Pol. Pharm. Drug Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Plotnikov, A., Kozer, N., Cohen, G., Carvalho, S., Duberstein, S., Almog, O., Solmesky, L.J., Shurrush, K.A., Babaev, I., and Benjamin, S. (2020). PRMT1 inhibition induces differentiation of colon cancer cells. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77028-8"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1615\/JEnvironPatholToxicolOncol.v28.i4.30","article-title":"Targeting Protein Kinase C (PKC) and Telomerase by Phenethyl Isothiocyanate (PEITC) Sensitizes PC-3 Cells Towards Chemotherapeutic Drug-Induced Apoptosis","volume":"28","author":"Mukherjee","year":"2009","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/mt.2010.216","article-title":"Sulforaphane Increases Drug-mediated Cytotoxicity Toward Cancer Stem-like Cells of Pancreas and Prostate","volume":"19","author":"Kallifatidis","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1158\/1535-7163.MCT-16-0515","article-title":"Fisetin enhances chemotherapeutic effect of cabazitaxel against human prostate cancer cells","volume":"15","author":"Mukhtar","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"356","DOI":"10.7150\/ijms.18382","article-title":"The effects and mechanism of YK-4-279 in combination with docetaxel on prostate cancer","volume":"14","author":"Yu","year":"2017","journal-title":"Int. J. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.4161\/cbt.7.8.6302","article-title":"Resveratrol displays converse dose-related effects on 5-fluorouracilevoked colon cancer cell apoptosis: The roles of caspase-6 and p53","volume":"7","author":"Chan","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/jcb.22601","article-title":"Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma","volume":"110","author":"Gatouillat","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1177\/1758834010376185","article-title":"De Choosing chemotherapy in patients with advanced urothelial cell cancer who are unfit to receive cisplatin-based chemotherapy","volume":"2","author":"Vos","year":"2010","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1039\/C5FO00120J","article-title":"The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells","volume":"6","author":"Bellesia","year":"2015","journal-title":"Food Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"603","DOI":"10.18632\/aging.100934","article-title":"Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies","volume":"8","author":"Pistritto","year":"2016","journal-title":"Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s00280-010-1413-y","article-title":"Sulforaphane potentiates oxaliplatin-induced cell growth inhibition in colorectal cancer cells via induction of different modes of cell death","volume":"67","author":"Kaminski","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"699","DOI":"10.3892\/ol.2014.2211","article-title":"5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-\u03b4","volume":"8","author":"Mhaidat","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.1128\/MCB.02261-07","article-title":"A New C-Terminal Cleavage Product of Procaspase-8, p30, Defines an Alternative Pathway of Procaspase-8 Activation","volume":"29","author":"Hoffmann","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_40","first-page":"832","article-title":"Overexpression of caspase-9 triggers its activation and apoptosis in vitro","volume":"47","author":"Milisav","year":"2006","journal-title":"Croat. Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Parrish, A.B., Freel, C.D., and Kornbluth, S. (2013). Cellular Mechanisms Controlling Caspase Activation and Function. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008672"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12703\/P7-18","article-title":"Autophagy in cancer","volume":"7","author":"Zhi","year":"2015","journal-title":"F1000Prime Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"456","DOI":"10.4103\/0366-6999.176069","article-title":"Autophagy in 5-fluorouracil therapy in gastrointestinal cancer: Trends and challenges","volume":"129","author":"Tang","year":"2016","journal-title":"Chin. Med. J. (Engl.)"},{"key":"ref_45","first-page":"250","article-title":"Detection and treatment of mycoplasma contamination in cultured cells","volume":"26","author":"Jung","year":"2003","journal-title":"Chang Gung Med. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/hlca.19480310608","article-title":"Synthese der racemischen und der optisch aktiven Formen des Sulforaphans","volume":"31","author":"Schmid","year":"1948","journal-title":"Helv. Chim. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bbrc.2017.07.078","article-title":"Inhibition of phosphatidylinositide 3-kinase ameliorates antiproliferation by benzyl isothiocyanate in human colon cancer cells","volume":"491","author":"Liu","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1023\/A:1009649025439","article-title":"Early features of apoptosis detected by four different flow cytometry assays","volume":"3","author":"Overbeeke","year":"1998","journal-title":"Apoptosis"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lin, J.Y., and Huang, H.I. (2020). Autophagy is induced and supports virus replication in Enterovirus A71-infected human primary neuronal cells. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-71970-3"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1007\/s13277-015-4258-5","article-title":"RIP1K and RIP3K provoked by shikonin induce cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: Necroptosis as a desperate programmed suicide pathway","volume":"37","author":"Shahsavari","year":"2016","journal-title":"Tumor Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/10\/3019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:03:48Z","timestamp":1760162628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/10\/3019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,19]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["molecules26103019"],"URL":"https:\/\/doi.org\/10.3390\/molecules26103019","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,19]]}}}