{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T17:23:12Z","timestamp":1775150592112,"version":"3.50.1"},"reference-count":78,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:00:00Z","timestamp":1625875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.<\/jats:p>","DOI":"10.3390\/ijms22147408","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:23:36Z","timestamp":1626049416000},"page":"7408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-5042","authenticated-orcid":false,"given":"Diana","family":"Duarte","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"given":"Armando","family":"Cardoso","sequence":"additional","affiliation":[{"name":"NeuroGen Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1200\/JCO.2011.40.3824","article-title":"The price we pay for progress: A meta-analysis of harms of newly approved anticancer drugs","volume":"30","author":"Niraula","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.tips.2013.06.005","article-title":"Cancer drug discovery by repurposing: Teaching new tricks to old dogs","volume":"34","author":"Gupta","year":"2013","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3332\/ecancer.2014.485","article-title":"The repurposing drugs in oncology (ReDO) project","volume":"8","author":"Pantziarka","year":"2014","journal-title":"Ecancermedicalscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.addr.2015.10.022","article-title":"Recent advances of cocktail chemotherapy by combination drug delivery systems","volume":"98","author":"Hu","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"S324","DOI":"10.4103\/0973-1482.235349","article-title":"Synergistic effect of thymoquinone and melatonin against breast cancer implanted in mice","volume":"14","author":"Odeh","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_8","first-page":"2381","article-title":"Curcumin and paclitaxel induce cell death in breast cancer cell lines","volume":"40","author":"Calaf","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.lfs.2018.04.035","article-title":"Apoptosis induction in human breast cancer cell lines by synergic effect of raloxifene and resveratrol through increasing proapoptotic genes","volume":"205","author":"Mirzapur","year":"2018","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3892\/ijo.2017.4052","article-title":"Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7","volume":"51","author":"Yao","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5903","DOI":"10.7314\/APJCP.2012.13.11.5903","article-title":"Synergistic effects of exemestane and aspirin on MCF-7 human breast cancer cells","volume":"13","author":"Hu","year":"2012","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_12","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_13","first-page":"113","article-title":"Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: The importance of scheduling","volume":"32","author":"Colomer","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/btm2.10082","article-title":"Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation","volume":"3","author":"Vogus","year":"2018","journal-title":"Bioeng. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the chou-talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1007\/s12272-018-1017-3","article-title":"Antipsychotic dopamine receptor antagonists, cancer, and cancer stem cells","volume":"41","author":"Roney","year":"2018","journal-title":"Arch. Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.mehy.2012.03.026","article-title":"Antipsychotic drugs: Pro-cancer or anti-cancer? A systematic review","volume":"79","author":"Fond","year":"2012","journal-title":"Med. Hypotheses"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1111","DOI":"10.1038\/cddis.2014.56","article-title":"Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer","volume":"5","author":"Zong","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127ra36","DOI":"10.1126\/scitranslmed.3003016","article-title":"Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma","volume":"4","author":"Munson","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abdelaleem, M., Ezzat, H., Osama, M., Megahed, A., Alaa, W., Gaber, A., Shafei, A., and Refaat, A. (2019). Prospects for repurposing CNS drugs for cancer treatment. Oncol. Rev., 13.","DOI":"10.4081\/oncol.2019.411"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3524","DOI":"10.1158\/1078-0432.CCR-15-2535","article-title":"Inhibition of FoxM1 -Mediated DNA repair by imipramine blue suppresses breast cancer growth and metastasis","volume":"22","author":"Rajamanickam","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1038\/onc.2015.291","article-title":"Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation","volume":"35","author":"Yang","year":"2016","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1038\/s41598-017-04796-1","article-title":"Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells","volume":"7","author":"Metts","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"51651","DOI":"10.18632\/oncotarget.10541","article-title":"Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia","volume":"7","author":"Laidlaw","year":"2016","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ejmech.2017.04.028","article-title":"Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules","volume":"134","author":"Ghorab","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1038\/srep27540","article-title":"Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents\u2014A drug repurposing strategy","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1158\/1535-7163.MCT-16-0169-T","article-title":"Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP 3 R","volume":"16","author":"Kang","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1164\/rccm.201207-1180OC","article-title":"Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer","volume":"186","author":"Yeh","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1124\/mol.62.2.210","article-title":"The Ca 2+ channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms","volume":"62","author":"Bertolesi","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1080\/15548627.2015.1082024","article-title":"Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation","volume":"11","author":"Ji","year":"2015","journal-title":"Autophagy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.canlet.2011.07.015","article-title":"Histone deacetylase inhibitor valproic acid suppresses the growth and increases the androgen responsiveness of prostate cancer cells","volume":"311","author":"Chou","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7715","DOI":"10.18632\/oncotarget.6802","article-title":"Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression","volume":"7","author":"Roca","year":"2016","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1002\/2211-5463.12223","article-title":"Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells","volume":"7","author":"Liu","year":"2017","journal-title":"FEBS Open Bio."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Saha, S., Yin, Y., Kim, K., Yang, G.-M., Dayem, A., Choi, H., and Cho, S.-G. (2017). Valproic acid induces endocytosis-mediated doxorubicin internalization and shows synergistic cytotoxic effects in hepatocellular carcinoma cells. Int. J. Mol. Sci., 18.","DOI":"10.20944\/preprints201703.0237.v1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5445","DOI":"10.2147\/IJN.S257700","article-title":"Recent Advances in Designing 5-Fluorouracil Delivery Systems: A Stepping Stone in the Safe Treatment of Colorectal Cancer","volume":"15","author":"Tayebi","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ben-Hamo, R., Zilberberg, A., Cohen, H., Bahar-Shany, K., Wachtel, C., Korach, J., Aviel-Ronen, S., Barshack, I., Barash, D., and Levanon, K. (2019). Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types. Npj Precis. Oncol., 3.","DOI":"10.1038\/s41698-019-0084-3"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Duarte, D., and Vale, N. (2020). New trends for antimalarial drugs: Synergism between antineoplastics and antimalarials on breast cancer cells. Biomolecules, 10.","DOI":"10.3390\/biom10121623"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.ccell.2018.12.011","article-title":"Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype","volume":"35","author":"Grolleman","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_39","unstructured":"(2021, April 09). Selegiline | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB01037."},{"key":"ref_40","unstructured":"(2021, April 09). Safinamide | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB06654."},{"key":"ref_41","unstructured":"(2021, April 09). Tolcapone | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00323."},{"key":"ref_42","unstructured":"(2021, April 09). Entacapone | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00494."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e332","DOI":"10.1038\/tp.2013.97","article-title":"Latrepirdine: Molecular mechanisms underlying potential therapeutic roles in Alzheimer\u2019s and other neurodegenerative diseases","volume":"3","author":"Bharadwaj","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_44","unstructured":"(2021, April 09). Fluphenazine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00623."},{"key":"ref_45","unstructured":"(2021, April 09). Thioridazine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00679."},{"key":"ref_46","unstructured":"(2021, April 09). Fluoxetine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00472."},{"key":"ref_47","unstructured":"(2021, April 09). Benzatropine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00245."},{"key":"ref_48","unstructured":"(2021, April 09). Carbidopa | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00190."},{"key":"ref_49","unstructured":"(2021, April 09). Bromocriptine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB01200."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.pnpbp.2015.01.009","article-title":"Evaluation of the dopamine \u03b2-hydroxylase (D\u03b2H) inhibitor nepicastat in participants who meet criteria for cocaine use disorder","volume":"59","author":"Bubar","year":"2015","journal-title":"Prog. Neuro Psychopharmacol. Biol. Psychiatry"},{"key":"ref_51","unstructured":"(2021, April 09). Scopolamine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00747."},{"key":"ref_52","unstructured":"(2021, April 09). Carbamazepine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00564."},{"key":"ref_53","unstructured":"(2021, April 09). Sertraline | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB01104."},{"key":"ref_54","unstructured":"(2021, April 09). Rivastigmine | DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB00989."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neuropharm.2014.12.018","article-title":"Allosteric activation of the 5-HT3AB receptor by mCPBG","volume":"91","author":"Miles","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/BF00178201","article-title":"The 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide facilitates noradrenaline release by blockade of \u03b12-adrenoceptors in the mouse brain cortex","volume":"349","author":"Schlicker","year":"1994","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: Visual analytics of multi-drug combination synergies","volume":"48","author":"Ianevski","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_59","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_60","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_61","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_62","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_63","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_64","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_65","first-page":"277","article-title":"Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice","volume":"33","author":"Zolokov","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.3892\/or.2016.5313","article-title":"Thioridazine elicits potent antitumor effects in colorectal cancer stem cells","volume":"37","author":"Zhang","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1023\/A:1026422111457","article-title":"Cell cycle G2\/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis","volume":"2","author":"Shu","year":"1997","journal-title":"Apoptosis"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"32101","DOI":"10.18632\/oncotarget.16646","article-title":"Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts","volume":"8","author":"Gwynne","year":"2017","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"299","DOI":"10.5306\/wjco.v6.i6.299","article-title":"Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer","volume":"6","author":"Bowie","year":"2015","journal-title":"World J. Clin. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e12402","DOI":"10.1111\/cpr.12402","article-title":"Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer","volume":"51","author":"Sun","year":"2018","journal-title":"Cell Prolif."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"53137","DOI":"10.18632\/oncotarget.10614","article-title":"Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer","volume":"7","author":"Hallett","year":"2016","journal-title":"Oncotarget"},{"key":"ref_72","first-page":"459","article-title":"Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases","volume":"9","author":"Xu","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s10549-008-0217-9","article-title":"MCF-7 breast carcinoma cells do not express caspase-3","volume":"117","year":"2009","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Sogawa, C., Eguchi, T., Tran, M.T., Ishige, M., Trin, K., Okusha, Y., Taha, E.A., Lu, Y., Kawai, H., and Sogawa, N. (2020). Antiparkinson drug benztropine suppresses tumor growth, circulating tumor cells, and metastasis by acting on SLC6A3\/DAT and reducing STAT3. Cancers, 12.","DOI":"10.20944\/preprints202002.0003.v1"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1476-5381.2011.01557.x","article-title":"Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: Clinical significance of in vitro and in vivo findings","volume":"165","author":"Dinan","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kapoor, A., Iqbal, M., Petropoulos, S., Ho, H.L., Gibb, W., and Matthews, S.G. (2013). Effects of Sertraline and Fluoxetine on P-Glycoprotein at Barrier Sites: In Vivo and In Vitro Approaches. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056525"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1211\/0022357043969","article-title":"Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds\u2014Implications for pharmacokinetics of selected substrates","volume":"56","author":"Schmitt","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Roell, K.R., Reif, D.M., and Motsinger-Reif, A.A. (2017). An introduction to terminology and methodology of chemical synergy\u2014perspectives from across disciplines. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00158"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7408\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:28:43Z","timestamp":1760164123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7408"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,10]]},"references-count":78,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147408"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147408","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,10]]}}}