Skip to content
2000
image of An Overview of the Potential Use of Selective Serotonin Reuptake Inhibitors (SSRIs) in Cancer Treatment

Abstract

Cancer is a major health problem and the second leading cause of death worldwide. Chemotherapy remains the mainstay therapeutic option to treat cancer patients, which consists of conventional, hormonal, and/or targeted therapies. However, the significant adverse effects, negative impact on patients’ quality of life, and high costs of some medications, as well as the challenges associated with developing new drugs, are prompting the scientific community to seek innovative and alternative treatment strategies. One such strategy is drug repurposing, the use of existing drugs, already approved for other medical conditions for cancer treatment, leveraging their known safety and toxicity profiles. Among these groups are the selective serotonin reuptake inhibitors (SSRIs) that target serotonin transporter (SERT). In this review, we presented the mechanism of action of SSRIs on the systems biology level, along with their network pharmacology related to protein-protein interactions. We also showed the association of SSRIs and SERT with various diseases, including several types of cancer. Knowing the expression of SERT in cancer and being a target for SSRIs, studies have been investigating the repurposing of SSRIs for cancer treatment. This review also presents a summary of several clinical and preclinical studies that have investigated the use of SSRIs either as single agents or in combination with conventional chemotherapy for cancer treatment, showing promising results. Collectively, they have shown the antiproliferative and growth inhibition effects on cancer cells and/or tumors. We also presented the mechanism(s) of action and pathways these drugs are acting in cancer, along with molecular changes in cellular proteins and enzymes.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096372733250611114329
2025-06-23
2025-10-13

  • From This Site

    /content/journals/ccdt/10.2174/0115680096372733250611114329
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Cancer Available from: https://www.who.int/health-topics/cancer#tab=tab_1
  2. Chhikara B.S. Parang K. Global Cancer Statistics 2022: the trends projection analysis. Chemical Biology Letters 2023 10 1 451
    [Google Scholar]
  3. Torre L.A. Siegel R.L. Ward E.M. Jemal A. Global cancer incidence and mortality rates and trends - An update. Cancer Epidemiol. Biomarkers Prev. 2016 25 1 16 27 26667886
    [Google Scholar]
  4. Niraula S. Seruga B. Ocana A. Shao T. Goldstein R. Tannock I.F. Amir E. The price we pay for progress: A meta-analysis of harms of newly approved anticancer drugs. J. Clin. Oncol. 2012 30 24 3012 3019 10.1200/JCO.2011.40.3824 22802313
    [Google Scholar]
  5. Gupta S.C. Sung B. Prasad S. Webb L.J. Aggarwal B.B. Cancer drug discovery by repurposing: Teaching new tricks to old dogs. Trends Pharmacol. Sci. 2013 34 9 508 517 10.1016/j.tips.2013.06.005 23928289
    [Google Scholar]
  6. Pantziarka P. Bouche G. Meheus L. Sukhatme V. Sukhatme V.P. Repurposing drugs in oncology (ReDO) - Cimetidine as an anti-cancer agent. Ecancermedicalscience 2014 8 485 10.3332/ecancer.2014.485 25525463
    [Google Scholar]
  7. Farha M.A. Brown E.D. Drug repurposing for antimicrobial discovery. Nat. Microbiol. 2019 4 4 565 577 10.1038/s41564‑019‑0357‑1 30833727
    [Google Scholar]
  8. Jampilek J. Drug repurposing to overcome microbial resistance. Drug Discov. Today 2022 27 7 2028 2041 10.1016/j.drudis.2022.05.006 35561965
    [Google Scholar]
  9. Singhal S. Maheshwari P. Krishnamurthy P.T. Patil V.M. Drug repurposing strategies for non-cancer to cancer therapeutics. Anticancer. Agents Med. Chem. 2022 22 15 2726 2756 10.2174/1871520622666220317140557 35301945
    [Google Scholar]
  10. Zheng Y. Chang X. Huang Y. He D. The application of antidepressant drugs in cancer treatment. Biomed. Pharmacother. 2023 157 113985 [PMID: 36402031
    [Google Scholar]
  11. Moorman P.G. Grubber J.M. Millikan R.C. Newman B. Antidepressant medications and their association with invasive breast cancer and carcinoma in situ of the breast. Epidemiology 2003 14 3 307 314 [PMID: 12859031
    [Google Scholar]
  12. Cotterchio M. Kreiger N. Darlington G. Steingart A. Antidepressant medication use and breast cancer risk. Am. J. Epidemiol. 2000 151 10 951 957 [PMID: 10853633
    [Google Scholar]
  13. Dalton S.O. Johansen C. Mellemkjaer L. Sørensen H.T. McLaughlin J.K. Olsen J. Olsen J.H. Antidepressant medications and risk for cancer. Epidemiology 2000 11 2 171 176 [PMID: 11021615
    [Google Scholar]
  14. Busby J. Mills K. Zhang S.D. Liberante F.G. Cardwell C.R. Selective serotonin reuptake inhibitor use and breast cancer survival: A population-based cohort study. Breast Cancer Res. 2018 20 1 4 [PMID: 29351761
    [Google Scholar]
  15. Boursi B. Lurie I. Haynes K. Mamtani R. Yang Y.X. Chronic therapy with selective serotonin reuptake inhibitors and survival in newly diagnosed cancer patients. Eur. J. Cancer Care 2018 27 1 e12666 10.1111/ecc.12666 28252230
    [Google Scholar]
  16. Lee H.K. Eom C.S. Kwon Y.M. Ahn J.S. Kim S. Park S.M. Meta-analysis: Selective serotonin reuptake inhibitors and colon cancer. Eur. J. Gastroenterol. Hepatol. 2012 24 10 1153 1157 [PMID: 22735609
    [Google Scholar]
  17. Haukka J. Sankila R. Klaukka T. Lonnqvist J. Niskanen L. Tanskanen A. Wahlbeck K. Tiihonen J. Incidence of cancer and antidepressant medication: Record linkage study. Int. J. Cancer 2010 126 1 285 296 [PMID: 19739257
    [Google Scholar]
  18. Lin C.F. Chan H.L. Hsieh Y.H. Liang H.Y. Chiu W.C. Huang K.Y. Lee Y. McIntyre R.S. Chen V.C.H. Endometrial cancer and antidepressants. Medicine 2016 95 29 e4178 10.1097/MD.0000000000004178 27442640
    [Google Scholar]
  19. Hsieh Y.H. Chiu W.C. Lin C.F. Chan H.L. Liang H.Y. Lee Y. McIntyre R.S. Chen V.C.H. Antidepressants and gastric cancer: A nationwide population-based nested case-control study. PLoS One 2015 10 11 e0143668 10.1371/journal.pone.0143668 26606417
    [Google Scholar]
  20. Lee M.J. Huang C.W. Chen Y.L. Yang Y.H. Chen V.C.H. Association between selective serotonin reuptake inhibitors and kidney cancer risk: A nationwide population‐based cohort study. Int. J. Cancer 2021 148 6 1331 1337 10.1002/ijc.33307 32965039
    [Google Scholar]
  21. Chen V.C.H. Lee M.J. Yang Y.H. Lu M.L. Chiu W.C. Dewey M.E. Selective serotonin reuptake inhibitors use and hepatocellular carcinoma in patients with alcohol use disorder. Drug Alcohol Depend. 2021 219 108495 10.1016/j.drugalcdep.2020.108495 33429293
    [Google Scholar]
  22. Murphy D.L. Lerner A. Rudnick G. Lesch K.P. Serotonin transporter: Gene, genetic disorders, and pharmacogenetics. Mol. Interv. 2004 4 2 109 123 10.1124/mi.4.2.8 15087484
    [Google Scholar]
  23. Subramanian A. Narayan R. Corsello S.M. Peck D.D. Natoli T.E. Lu X. Gould J. Davis J.F. Tubelli A.A. Asiedu J.K. Lahr D.L. Hirschman J.E. Liu Z. Donahue M. Julian B. Khan M. Wadden D. Smith I.C. Lam D. Liberzon A. Toder C. Bagul M. Orzechowski M. Enache O.M. Piccioni F. Johnson S.A. Lyons N.J. Berger A.H. Shamji A.F. Brooks A.N. Vrcic A. Flynn C. Rosains J. Takeda D.Y. Hu R. Davison D. Lamb J. Ardlie K. Hogstrom L. Greenside P. Gray N.S. Clemons P.A. Silver S. Wu X. Zhao W.N. Read-Button W. Wu X. Haggarty S.J. Ronco L.V. Boehm J.S. Schreiber S.L. Doench J.G. Bittker J.A. Root D.E. Wong B. Golub T.R. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell 2017 171 6 1437 1452.e17 10.1016/j.cell.2017.10.049 29195078
    [Google Scholar]
  24. Hajjo R. Tropsha A. A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality. Pharm. Res. 2020 37 11 212 10.1007/s11095‑020‑02930‑9 33025261
    [Google Scholar]
  25. Hajjo R. Sabbah D. Tropsha A. Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects. Pathogens 2022 11 7 743 10.3390/pathogens11070743 35889989
    [Google Scholar]
  26. Hajjo R. Setola V. Roth B.L. Tropsha A. Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential cognition enhancers. J. Med. Chem. 2012 55 12 5704 5719 [PMID: 22537153
    [Google Scholar]
  27. Hajjo R. Momani E. Sabbah D.A. Baker N. Tropsha A. Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes. NPJ Vaccines 2023 8 1 129 [PMID: 37658087
    [Google Scholar]
  28. Guan L. Yuan S. Ma J. Liu H. Huang L. Zhang F. Neurokinin-1 receptor is highly expressed in cervical cancer and its antagonist induces cervical cancer cell apoptosis. Eur. J. Histochem. 2023 67 1 3570 [PMID: 36629320
    [Google Scholar]
  29. Coveñas R. Muñoz M. Cancer progression and substance P. Histol. Histopathol. 2014 29 7 881 890 [PMID: 24535838
    [Google Scholar]
  30. He L. Fu Y. Tian Y. Wang X. Zhou X. Ding R.B. Qi X. Bao J. Antidepressants as autophagy modulators for cancer therapy. Molecules 2023 28 22 7594 10.3390/molecules28227594 38005316
    [Google Scholar]
  31. Zhong P. Nakata K. Oyama K. Higashijima N. Sagara A. Date S. Luo H. Hayashi M. Kubo A. Wu C. He S. Yamamoto T. Koikawa K. Iwamoto C. Abe T. Ikenaga N. Ohuchida K. Morisaki T. Oda Y. Kuba K. Nakamura M. Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells. J. Exp. Clin. Cancer Res. 2024 43 1 138 10.1186/s13046‑024‑03060‑5 38715057
    [Google Scholar]
  32. Fernández-Nogueira P. Noguera-Castells A. Fuster G. Recalde-Percaz L. Moragas N. López-Plana A. Enreig E. Jauregui P. Carbó N. Almendro V. Gascón P. Bragado P. Mancino M. Histamine receptor 1 inhibition enhances antitumor therapeutic responses through extracellular signal-regulated kinase (ERK) activation in breast cancer. Cancer Lett. 2018 424 70 83 10.1016/j.canlet.2018.03.014 29548821
    [Google Scholar]
  33. Joo S.H. Chun K.S. Therapeutic strategies for colorectal cancer: Antitumor efficacy of dopamine D2 receptor antagonists. Toxicol. Res. 2024 40 4 533 540 10.1007/s43188‑024‑00259‑8 39345737
    [Google Scholar]
  34. Pavletić P. Semeano A. Yano H. Bonifazi A. Giorgioni G. Piergentili A. Quaglia W. Sabbieti M.G. Agas D. Santoni G. Pallini R. Ricci-Vitiani L. Sabato E. Vistoli G. Del Bello F. Highly potent and selective dopamine D 4 receptor antagonists potentially useful for the treatment of glioblastoma. J. Med. Chem. 2022 65 18 12124 12139 10.1021/acs.jmedchem.2c00840 36098685
    [Google Scholar]
  35. Weissenrieder J.S. Neighbors J.D. Mailman R.B. Hohl R.J. Cancer and the dopamine D2 receptor: A pharmacological perspective. J. Pharmacol. Exp. Ther. 2019 370 1 111 126 10.1124/jpet.119.256818 31000578
    [Google Scholar]
  36. Sundahl N. Clarisse D. Bracke M. Offner F. Berghe W.V. Beck I.M. Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments. Oncoscience 2016 3 7-8 188 202 10.18632/oncoscience.315 27713909
    [Google Scholar]
  37. Bilir A. Erguven M. Yazihan N. Aktas E. Oktem G. Sabanci A. Enhancement of vinorelbine-induced cytotoxicity and apoptosis by clomipramine and lithium chloride in human neuroblastoma cancer cell line SH-SY5Y. J. Neurooncol. 2010 100 3 385 395 10.1007/s11060‑010‑0209‑6 20467784
    [Google Scholar]
  38. Bongiorno-Borbone L. Giacobbe A. Compagnone M. Eramo A. De Maria R. Peschiaroli A. Melino G. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells. Oncotarget 2015 6 19 16926 16938 10.18632/oncotarget.4700 26219257
    [Google Scholar]
  39. Huang W. Yang S. Cheng Y.S. Sima N. Sun W. Shen M. Braisted J.C. Lu W. Zheng W. Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression. Front. Oncol. 2022 12 1068443 10.3389/fonc.2022.1068443 36439493
    [Google Scholar]
  40. An L. Li D.D. Chu H.X. Zhang Q. Wang C.L. Fan Y.H. Song Q. Ma H.D. Feng F. Zhao Q.C. Terfenadine combined with epirubicin impedes the chemo-resistant human non-small cell lung cancer both in vitro and in vivo through EMT and Notch reversal. Pharmacol. Res. 2017 124 105 115 10.1016/j.phrs.2017.07.021 28754458
    [Google Scholar]
  41. Baniya M.K. Kim E.H. Chun K.S. Terfenadine, a histamine H1 receptor antagonist, induces apoptosis by suppressing STAT3 signaling in human colorectal cancer HCT116 cells. Front. Pharmacol. 2024 15 1418266 10.3389/fphar.2024.1418266 38939837
    [Google Scholar]
  42. Nicolau-Galmés F. Asumendi A. Alonso-Tejerina E. Pérez-Yarza G. Jangi S.M. Gardeazabal J. Arroyo-Berdugo Y. Careaga J.M. Díaz-Ramón J.L. Apraiz A. Boyano M.D. Terfenadine induces apoptosis and autophagy in melanoma cells through ROS-dependent and -independent mechanisms. Apoptosis 2011 16 12 1253 1267 10.1007/s10495‑011‑0640‑y 21861192
    [Google Scholar]
  43. Potera M.E. Lookingbill D.P. Stryker J.A. Prophylaxis of radiation dermatitis with a topical cortisone cream. Radiology 1982 143 3 775 777 10.1148/radiology.143.3.7079509 7079509
    [Google Scholar]
  44. Ribeiro E. Araújo D. Pereira M. Lopes B. Sousa P. Sousa A.C. Coelho A. Rêma A. Alvites R. Faria F. Oliveira C. Porto B. Maurício A.C. Amorim I. Vale N. Repurposing benztropine, natamycin, and nitazoxanide using drug combination and characterization of gastric cancer cell lines. Biomedicines 2023 11 3 799 10.3390/biomedicines11030799 36979779
    [Google Scholar]
  45. Cui J. Hollmén M. Li L. Chen Y. Proulx S.T. Reker D. Schneider G. Detmar M. New use of an old drug: Inhibition of breast cancer stem cells by benztropine mesylate. Oncotarget 2017 8 1 1007 1022 10.18632/oncotarget.13537 27894093
    [Google Scholar]
  46. Cerles O. Gonçalves T.C. Chouzenoux S. Benoit E. Schmitt A. Bennett Saidu N.E. Kavian N. Chéreau C. Gobeaux C. Weill B. Coriat R. Nicco C. Batteux F. Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth. Acta Neuropathol. Commun. 2019 7 1 9 10.1186/s40478‑019‑0657‑y 30657060
    [Google Scholar]
  47. Sogawa C. Eguchi T. Tran M.T. Ishige M. Trin K. Okusha Y. Taha E.A. Lu Y. Kawai H. Sogawa N. Takigawa M. Calderwood S.K. Okamoto K. Kozaki K. Antiparkinson drug benztropine suppresses tumor growth, circulating tumor cells, and metastasis by acting on SLC6A3/DAT and reducing STAT3. Cancers 2020 12 2 523 10.3390/cancers12020523 32102440
    [Google Scholar]
  48. Bardaweel S.K. Al-salamat H. Hajjo R. Sabbah D. Almutairi S. Unveiling the intricacies of monoamine oxidase-A (MAO-A) inhibition in colorectal cancer: Computational systems biology, expression patterns, and the anticancer therapeutic potential. ACS Omega 2024 9 33 35703 35717 10.1021/acsomega.4c04100 39184489
    [Google Scholar]
  49. Sirtori C.R. Rodriguez G.A. Guarino M.J. Azarnoff R.S. Boulos B.M. Effect of trans-1,4-bis-2-dichlorbenzyl-aminoethyl-cyclohexane (AY-9944) on the experimental brain tumor G26A. Arzneimittelforschung 1972 22 5 914 916 [PMID: 4626014
    [Google Scholar]
  50. Malpeli G. Barbi S. Innamorati G. Alloggio M. Filippini F. Decimo I. Castelli C. Perris R. Bencivenga M. Landscape of druggable molecular pathways downstream of genomic CDH1/cadherin-1 alterations in gastric cancer. J. Pers. Med. 2022 12 12 2006 10.3390/jpm12122006 36556227
    [Google Scholar]
  51. Ogawa T. Sugidachi A. Tanaka N. Fujimoto K. Asai F. Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444. Eur. J. Pharmacol. 2002 457 2-3 107 114 10.1016/S0014‑2999(02)02654‑7 12464356
    [Google Scholar]
  52. Long Z. Chen B. Liu Q. Zhao J. Yang Z. Dong X. Xia L. Huang S. Hu X. Song B. Li L. The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activat-ing the JNK pathway and blocking autophagic flux. Oncotarget 2106 7 27 42059 42070 10.18632/oncotarget.9806 27275542
    [Google Scholar]
  53. Liu Z. Cheng Q. Ma X. Song M. Suppressing Effect of Na+/Ca2+ Exchanger (NCX) Inhibitors on the Growth of Melanoma Cells. Int. J. Mol. Sci. 2022 23 2 901 10.3390/ijms23020901 35055084
    [Google Scholar]
  54. Hu H.J. Wang S.S. Wang Y.X. Liu Y. Feng X.M. Shen Y. Zhu L. Chen H.Z. Song M. Blockade of the forward Na+/Ca2+ exchanger suppresses the growth of glioblastoma cells through Ca2+‐mediated cell death. Br. J. Pharmacol. 2019 176 15 2691 2707 10.1111/bph.14692 31034096
    [Google Scholar]
  55. Pelzl L. Hosseinzadeh Z. Alzoubi K. Al-Maghout T. Schmidt S. Stournaras C. Lang F. Impact of Na+/Ca2+ exchangers on therapy resistance of ovary carcinoma cells. Cell. Physiol. Biochem. 2015 37 5 1857 1868 10.1159/000438547 26584285
    [Google Scholar]
  56. Moody T.W. Leyton J. John C. Sigma ligands inhibit the growth of small cell lung cancer cells. Life Sci. 2000 66 20 1979 1986 10.1016/S0024‑3205(00)00523‑3 10821122
    [Google Scholar]
  57. Alwhaibi A. Alsanea S. Almadi B. Al-sabhan J. Alosaimi F.D. Androgen deprivation therapy and depression in the prostate cancer patients: Review of risk and pharmacological management. Aging Male 2022 25 1 101 124 10.1080/13685538.2022.2053954 35343371
    [Google Scholar]
  58. Balakrishna P. George S. Hatoum H. Mukherjee S. Serotonin pathway in cancer. Int. J. Mol. Sci. 2021 22 3 1268 10.3390/ijms22031268 33525332
    [Google Scholar]
  59. Abualsaud N. Caprio L. Galli S. Krawczyk E. Alamri L. Zhu S. Gallicano G.I. Kitlinska J. Neuropeptide Y/Y5 receptor pathway stimulates neuroblastoma cell motility through rhoa activation. Front. Cell Dev. Biol. 2021 8 627090 10.3389/fcell.2020.627090 33681186
    [Google Scholar]
  60. Lin S. Li Y. Sun X. Chen Q. Huang S. Lin S. Cai S. Update on the role of neuropeptide Y and other related factors in breast cancer and osteoporosis. Front. Endocrinol. 2021 12 705499 10.3389/fendo.2021.705499 34421823
    [Google Scholar]
  61. Lu C. Mahajan A. Hong S.H. Galli S. Zhu S. Tilan J.U. Abualsaud N. Adnani M. Chung S. Elmansy N. Rodgers J. Rodriguez O. Albanese C. Wang H. Regan M. Zgonc V. Blancato J. Krawczyk E. Gallicano G.I. Girgis M. Cheema A. Iżycka-Świeszewska E. Cavalli L.R. Pack S.D. Kitlinska J. Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma. Nat. Commun. 2022 13 1 2323 10.1038/s41467‑022‑29898‑x 35484119
    [Google Scholar]
  62. Lu C. Mahajan A. Hong S.H. Galli S. Zhu S. Tilan J.U. Abualsaud N. Adnani M. Chung S. Elmansy N. Rodgers J. Rodriguez O. Albanese C. Wang H. Regan M. Zgonc V. Blancato J. Krawczyk E. Gallicano G.I. Girgis M. Cheema A. Iżycka-Świeszewska E. Cavalli L.R. Pack S.D. Kitlinska J. Publisher Correction: Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma. Nat. Commun. 2022 13 1 2729 10.1038/s41467‑022‑30473‑7 35550518
    [Google Scholar]
  63. Cınar V. Hamurcu Z. Guler A. Nurdinov N. Ozpolat B. Serotonin 5-HT7 receptor is a biomarker poor prognostic factor and induces proliferation of triple-negative breast cancer cells through FOXM1. Breast Cancer 2022 29 6 1106 1120 10.1007/s12282‑022‑01391‑9 36006564
    [Google Scholar]
  64. Du Y. Li K. Wang X. Kaushik A.C. Junaid M. Wei D. Identification of chlorprothixene as a potential drug that induces apoptosis and autophagic cell death in acute myeloid leukemia cells. FEBS J. 2020 287 8 1645 1665 10.1111/febs.15102 31625692
    [Google Scholar]
  65. Yu B. Liu L. Yan J. Cao J. Cao Y. Effect of berbamine on invasion and metastasis of human liver cancer SMMC-7721 cells and its possible mechanism. Anticancer Drugs 2022 33 1 e178 e185 10.1097/CAD.0000000000001179 34321418
    [Google Scholar]
  66. Zhu C. Lu Y. Wang S. Song J. Ding Y. Wang Y. Dong C. Liu J. Qiu W. Qi W. Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway. Sci. Rep. 2024 14 1 6050 10.1038/s41598‑024‑56431‑5 38480798
    [Google Scholar]
  67. Huang C. Lan W. Fraunhoffer N. Meilerman A. Iovanna J. Santofimia-Castaño P. Dissecting the anticancer mechanism of trifluoperazine on pancreatic ductal adenocarcinoma. Cancers 2019 11 12 1869 10.3390/cancers11121869 31769431
    [Google Scholar]
  68. Xia Y. Jia C. Xue Q. Jiang J. Xie Y. Wang R. Ran Z. Xu F. Zhang Y. Ye T. Antipsychotic drug trifluoperazine suppresses colorectal cancer by inducing G0/G1 arrest and apoptosis. Front. Pharmacol. 2019 10 1029 10.3389/fphar.2019.01029 31572198
    [Google Scholar]
  69. Bani N. Rahmani F. Shakour N. Amerizadeh F. Khalili-Tanha G. Khazaei M. Hassanian S.M. Kerachian M.A. Abbaszadegan M.R. Mojarad M. Hadizadeh F. Ferns G.A. Avan A. Wortmannin inhibits cell growth and induces apoptosis in colorectal cancer cells by suppressing the PI3K/AKT pathway. Anticancer. Agents Med. Chem. 2024 24 12 916 927 10.2174/0118715206296355240325113920 38584531
    [Google Scholar]
  70. Hajjo R. Sabbah D.A. Bardaweel S.K. Chemocentric informatics analysis: Dexamethasone versus combination therapy for COVID-19. ACS Omega 2020 5 46 29765 29779 10.1021/acsomega.0c03597 33251412
    [Google Scholar]
  71. Bardaweel S.K. Hajjo R. Sabbah D.A. Sitagliptin: A potential drug for the treatment of COVID-19? Acta Pharm. 2021 71 2 175 184 10.2478/acph‑2021‑0013 33151168
    [Google Scholar]
  72. Sabbah D.A. Hajjo R. Sweidan K. Zhong H.A. An integrative informatics approach to explain the mechanism of action of N1-(anthraquinon-2-yl) amidrazones as BCR/ABL inhibitors. Curr. Computeraided Drug Des. 2021 17 6 817 830 10.2174/1573409916666200819113444 32814537
    [Google Scholar]
  73. Walker F.R. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: Do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology 2013 67 304 317 10.1016/j.neuropharm.2012.10.002 23085335
    [Google Scholar]
  74. Mikkelsen N. Damkier P. Pedersen S.A. Serotonin syndrome - A focused review. Basic Clin. Pharmacol. Toxicol. 2023 133 2 124 129 10.1111/bcpt.13912 37309284
    [Google Scholar]
  75. Lochmann D. Richardson T. Selective serotonin reuptake inhibitors. Handb. Exp. Pharmacol. 2018 250 135 144 10.1007/164_2018_172 30838457
    [Google Scholar]
  76. Cytoscape Available from: https://cytoscape.org/
  77. Welcome to STRING Available from: https://string-db.org/
  78. Comparative toxicogenomics database Available from: https://ctdbase.org
  79. Schultz A. Saville B.R. Marsh J.A. Snelling T.L. An introduction to clinical trial design. Paediatr. Respir. Rev. 2019 32 30 35 [PMID: 31427159
    [Google Scholar]
  80. Al Khzem A.H. Gomaa M.S. Alturki M.S. Tawfeeq N. Sarafroz M. Alonaizi S.M. Al Faran A. Alrumaihi L.A. Alansari F.A. Alghamdi A.A. Drug repurposing for cancer treatment: A comprehensive review. Int. J. Mol. Sci. 2024 25 22 12441 10.3390/ijms252212441 39596504
    [Google Scholar]
  81. Abumansour H. Abusara O.H. Khalil W. Abul-Futouh H. Ibrahim A.I.M. Harb M.K. Abulebdah D.H. Ismail W.H. Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line. Naunyn Schmiedebergs Arch. Pharmacol. 2024 397 9 6963 6973 10.1007/s00210‑024‑03075‑x 38613572
    [Google Scholar]
  82. Wu L. Leng D. Cun D. Foged C. Yang M. Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens. J. Control. Release 2017 260 78 91 10.1016/j.jconrel.2017.05.023 28527735
    [Google Scholar]
  83. Fisusi F.A. Akala E.O. Drug combinations in breast cancer therapy. Pharm. Nanotechnol. 2019 7 1 3 23 10.2174/2211738507666190122111224 30666921
    [Google Scholar]
  84. Liu L. Huang X. Shi F. Song J. Guo C. Yang J. Liang T. Bai X. Combination therapy for pancreatic cancer: Anti-PD-(L)1-based strategy. J. Exp. Clin. Cancer Res. 2022 41 1 56 10.1186/s13046‑022‑02273‑w 35139879
    [Google Scholar]
  85. Abusara O.H. Ibrahim A.I.M. Issa H. Hammad A.M. Ismail W.H. In vitro evaluation of ALDH1A3-affinic compounds on breast and prostate cancer cell lines as single treatments and in combination with doxorubicin. Curr. Issues Mol. Biol. 2023 45 3 2170 2181 10.3390/cimb45030139 36975509
    [Google Scholar]
  86. Al-Ali L. Al-Ani R.J. Saleh M.M. Hammad A.M. Abuarqoub D.A. Abu-Irmaileh B. Naser A.Y. Najdawi M.M. Abbas M.M. Alyoussef Alkrad J. Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia. Saudi Pharm. J. 2024 32 2 101931 10.1016/j.jsps.2023.101931 38298828
    [Google Scholar]
  87. Combination chemotherapy plus fluoxetine in treating patients with advanced or recurrent non-small cell lung cancer NCT00005850 2016
  88. Fluoxetine for the modification of colorectal tumor immune cells before surgery in patients with colorectal cancer NCT06225011 2025
  89. A proof-of-concept clinical trial assessing the safety of the coordinated undermining of survival paths by 9 repurposed drugs combined with metronomic temozolomide (CUSP9v3 Treatment Protocol) for recurrent glioblastoma NCT02770378 2021
  90. Sertraline and cytosine arabinoside in adults with relapsed and refractory AML NCT02891278 2023
  91. Hsu L.C. Tu H.F. Hsu F.T. Yueh P.F. Chiang I.T. Beneficial effect of fluoxetine on anti-tumor progression on hepatocellular carcinoma and non-small cell lung cancer bearing animal model. Biomed. Pharmacother. 2020 126 110054 10.1016/j.biopha.2020.110054 32145588
    [Google Scholar]
  92. Shao S. Zhuang X. Zhang L. Qiao T. Antidepressants fluoxetine mediates endoplasmic reticulum stress and autophagy of non–small cell lung cancer cells through the ATF4-AKT-mTOR signaling pathway. Front. Pharmacol. 2022 13 904701 10.3389/fphar.2022.904701 35620287
    [Google Scholar]
  93. Yang Z. Li Z. Guo Z. Ren Y. Zhou T. Xiao Z. Duan J. Han C. Cheng Y. Xu F. Antitumor effect of fluoxetine on chronic stress-promoted lung cancer growth via suppressing kynurenine pathway and enhancing cellular immunity. Front. Pharmacol. 2021 12 685898 10.3389/fphar.2021.685898 34413774
    [Google Scholar]
  94. Kannen V. Garcia S.B. Silva W.A. Gasser M. Mönch R. Alho E.J.L. Heinsen H. Scholz C.J. Friedrich M. Heinze K.G. Waaga-Gasser A.M. Stopper H. Oncostatic effects of fluoxetine in experimental colon cancer models. Cell. Signal. 2015 27 9 1781 1788 10.1016/j.cellsig.2015.05.008 26004136
    [Google Scholar]
  95. Kannen V. Marini T. Turatti A. Carvalho M.C. Brandão M.L. Jabor V.A.P. Bonato P.S. Ferreira F.R. Zanette D.L. Silva W.A. Garcia S.B. Fluoxetine induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats. Toxicol. Lett. 2011 204 2-3 134 140 10.1016/j.toxlet.2011.04.024 21554931
    [Google Scholar]
  96. Kannen V. Hintzsche H. Zanette D.L. Silva W.A. Garcia S.B. Waaga-Gasser A.M. Stopper H. Antiproliferative effects of fluoxetine on colon cancer cells and in a colonic carcinogen mouse model. PLoS One 2012 7 11 e50043 10.1371/journal.pone.0050043 23209640
    [Google Scholar]
  97. Marcinkute M. Afshinjavid S. Fatokun A.A. Javid F.A. Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells. Eur. J. Pharmacol. 2019 857 172441 10.1016/j.ejphar.2019.172441 31181210
    [Google Scholar]
  98. Lupu D. In vitro effects of fluoxetine and norfluoxetine on breast cancer proliferation. Farmacia 2017 65 532 536
    [Google Scholar]
  99. Krishnan A. Hariharan R. Nair S.A. Pillai M.R. Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochem. Pharmacol. 2008 75 10 1924 1934 10.1016/j.bcp.2008.02.013 18371935
    [Google Scholar]
  100. Bowie M. Pilie P. Wulfkuhle J. Lem S. Hoffman A. Desai S. Petricoin E. Carter A. Ambrose A. Seewaldt V. Yu D. Ibarra Drendall C. Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer. World J. Clin. Oncol. 2015 6 6 299 311 10.5306/wjco.v6.i6.299 26677444
    [Google Scholar]
  101. Sun D. Zhu L. Zhao Y. Jiang Y. Chen L. Yu Y. Ouyang L. Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Prolif. 2018 51 2 e12402 10.1111/cpr.12402 29094413
    [Google Scholar]
  102. Bavadekar S. Panchal P. Hanbashi A. Vansal S. Cytotoxic ef-fects of selective serotonin‐ and serotonin‐norepinephrine reuptake inhibitors on human metastatic breast cancer cell line, MCF‐7 (842.3). FASEB J. 2014 28 S1 842.3 10.1096/fasebj.28.1_supplement.842.3
    [Google Scholar]
  103. Mun A.R. Lee S.J. Kim G.B. Kang H.S. Kim J.S. Kim S.J. Fluoxetine-induced apoptosis in hepatocellular carcinoma cells. Anticancer Res. 2013 33 9 3691 3697 [PMID: 24023297
    [Google Scholar]
  104. Chen W.T. Hsu F-T. Liu Y-C. Chen C-H. Hsu L-C. Lin S-S. Fluoxetine induces apoptosis through extrinsic/intrinsic pathways and inhibits ERK/NF-κB-modulated anti-apoptotic and invasive potential in hepatocellular carcinoma cells in vitro. Int. J. Mol. Sci. 2019 20 3 757 10.3390/ijms20030757
    [Google Scholar]
  105. Zhang H. Xu H. Tang Q. Bi F. The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells. Anticancer Drugs 2021 32 8 793 801 10.1097/CAD.0000000000001067 33675613
    [Google Scholar]
  106. Serafeim A. Holder M.J. Grafton G. Chamba A. Drayson M.T. Luong Q.T. Bunce C.M. Gregory C.D. Barnes N.M. Gordon J. Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. Blood 2003 101 8 3212 3219 10.1182/blood‑2002‑07‑2044 12515726
    [Google Scholar]
  107. Frick L.R. Palumbo M.L. Zappia M.P. Brocco M.A. Cremaschi G.A. Genaro A.M. Inhibitory effect of fluoxetine on lymphoma growth through the modulation of antitumor T-cell response by serotonin-dependent and independent mechanisms. Biochem. Pharmacol. 2008 75 9 1817 1826 10.1016/j.bcp.2008.01.015 18342838
    [Google Scholar]
  108. Frick L.R. Rapanelli M. Arcos M.L.B. Cremaschi G.A. Genaro A.M. Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice. Eur. J. Pharmacol. 2011 659 2-3 265 272 10.1016/j.ejphar.2011.03.037 21497159
    [Google Scholar]
  109. Chamba A. Holder M.J. Jarrett R.F. Shield L. Toellner K.M. Drayson M.T. Barnes N.M. Gordon J. SLC6A4 expression and anti-proliferative responses to serotonin transporter ligands chlomipramine and fluoxetine in primary B-cell malignancies. Leuk. Res. 2010 34 8 1103 1106 10.1016/j.leukres.2010.03.007 20363025
    [Google Scholar]
  110. Liu K.H. Yang S.T. Lin Y.K. Lin J.W. Lee Y.H. Wang J.Y. Hu C.J. Lin E.Y. Chen S.M. Then C.K. Shen S.C. Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis. Oncotarget 2015 6 7 5088 5101 10.18632/oncotarget.3243 25671301
    [Google Scholar]
  111. Levkovitz Y. Gil-Ad I. Zeldich E. Dayag M. Weizman A. A. Dif-ferential induction of apoptosis by antidepressants in glioma and neu-roblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement. J. Mol. Neurosci 2005 27 1 029 042 10.1385/JMN:27:1:029 16055945
    [Google Scholar]
  112. Bibbo’ S. Lamolinara A. Capone E. Purgato S. Tsakaneli A. Panella V. Sallese M. Rossi C. Ciufici P. Nieddu V. De Laurenzi V. Iezzi M. Perini G. Sala G. Sala A. Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac. Oncogenesis 2020 9 1 3 10.1038/s41389‑019‑0186‑3 31900399
    [Google Scholar]
  113. Grygier B. Arteta B. Kubera M. Basta-Kaim A. Budziszewska B. Leśkiewicz M. Curzytek K. Duda W. Lasoń W. Maes M. Inhibitory effect of antidepressants on B16F10 melanoma tumor growth. Pharmacol. Rep. 2013 65 3 672 681 10.1016/S1734‑1140(13)71045‑4 23950590
    [Google Scholar]
  114. Abdul M. Logothetis C.J. Hoosein N.M. Growth-inhibitory effects of serotonin uptake inhibitors on human prostate carcinoma cell lines. J. Urol. 1995 154 1 247 250 10.1016/S0022‑5347(01)67288‑4 7776439
    [Google Scholar]
  115. Chen L. Ji Y. Li A. Liu B. Shen K. Su R. Ma Z. Zhang W. Wang Q. Zhu Y. Xue W. High-throughput drug screening identifies fluoxetine as a potential therapeutic agent for neuroendocrine prostate cancer. Front. Oncol. 2023 13 1085569 10.3389/fonc.2023.1085569 36994207
    [Google Scholar]
  116. Lee C.S. Kim Y.J. Jang E.R. Kim W. Myung S.C. Fluoxetine induces apoptosis in ovarian carcinoma cell line OVCAR-3 through reactive oxygen species-dependent activation of nuclear factor-kappaB. Basic Clin. Pharmacol. Toxicol. 2010 106 6 446 453 10.1111/j.1742‑7843.2009.00509.x 20050848
    [Google Scholar]
  117. Po W.W. Thein W. Khin P.P. Khing T.M. Han K.W.W. Park C.H. Sohn U.D. Fluoxetine simultaneously induces both apoptosis and autophagy in human gastric adenocarcinoma cells. Biomol. Ther. 2020 28 2 202 210 10.4062/biomolther.2019.103 31522488
    [Google Scholar]
  118. Khin P.P. Po W.W. Thein W. Sohn U.D. Apoptotic effect of fluoxetine through the endoplasmic reticulum stress pathway in the human gastric cancer cell line AGS. Naunyn Schmiedebergs Arch. Pharmacol. 2020 393 4 537 549 10.1007/s00210‑019‑01739‑7 31707450
    [Google Scholar]
  119. Zinnah K. Seol J.W. Park S.Y. Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int. J. Mol. Med. 2020 46 2 795 805 10.3892/ijmm.2020.4635 32626921
    [Google Scholar]
  120. Jiang X. Lu W. Shen X. Wang Q. Lv J. Liu M. Cheng F. Zhao Z. Pang X. Repurposing sertraline sensitizes non–small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight 2018 3 11 e98921 10.1172/jci.insight.98921 29875309
    [Google Scholar]
  121. Ye D. Xu H. Xia H. Zhang C. Tang Q. Bi F. Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment. J. Exp. Clin. Cancer Res. 2021 40 1 173 10.1186/s13046‑021‑01971‑1 34006301
    [Google Scholar]
  122. Gil-Ad I. Zolokov A. Lomnitski L. Taler M. Bar M. Luria D. Ram E. Weizman A. Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice. Int. J. Oncol. 2008 33 2 277 286 [PMID: 18636148
    [Google Scholar]
  123. Duarte D. Cardoso A. Vale N. Synergistic growth inhibition of HT-29 colon and MCF-7 breast cancer cells with simultaneous and sequential combinations of antineoplastics and CNS drugs. Int. J. Mol. Sci. 2021 22 14 7408 10.3390/ijms22147408 34299028
    [Google Scholar]
  124. Lin C.J. Robert F. Sukarieh R. Michnick S. Pelletier J. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res. 2010 70 8 3199 3208 10.1158/0008‑5472.CAN‑09‑4072 20354178
    [Google Scholar]
  125. Katiyar S. Liu E. Knutzen C.A. Lang E.S. Lombardo C.R. Sankar S. Toth J.I. Petroski M.D. Ronai Z. Chiang G.G. REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO Rep. 2009 10 8 866 872 [PMID: 19557001
    [Google Scholar]
  126. Gwynne W.D. Hallett R.M. Girgis-Gabardo A. Bojovic B. Dvorkin-Gheva A. Aarts C. Dias K. Bane A. Hassell J.A. Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts. Oncotarget 2017 8 19 32101 32116 10.18632/oncotarget.16646 28404880
    [Google Scholar]
  127. Amson R. Pece S. Lespagnol A. Vyas R. Mazzarol G. Tosoni D. Colaluca I. Viale G. Rodrigues-Ferreira S. Wynendaele J. Chaloin O. Hoebeke J. Marine J.C. Di Fiore P.P. Telerman A. Reciprocal repression between P53 and TCTP. Nat. Med. 2012 18 1 91 99 10.1038/nm.2546 22157679
    [Google Scholar]
  128. Chen S. Xuan J. Wan L. Lin H. Couch L. Mei N. Dobrovolsky V.N. Guo L. Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol. Sci. 2014 137 2 404 415 [PMID: 24194395
    [Google Scholar]
  129. Kuwahara J. Yamada T. Egashira N. Ueda M. Zukeyama N. Ushio S. Masuda S. Comparison of the anti-tumor effects of selective serotonin reuptake inhibitors as well as serotonin and norepinephrine reuptake inhibitors in human hepatocellular carcinoma cells. Biol. Pharm. Bull. 2015 38 9 1410 1414 [PMID: 26328498
    [Google Scholar]
  130. Amit B.H. Gil-Ad I. Taler M. Bar M. Zolokov A. Weizman A. Proapoptotic and chemosensitizing effects of selective serotonin reuptake inhibitors on T cell lymphoma/leukemia (Jurkat) in vitro. Eur. Neuropsychopharmacol. 2009 19 10 726 734 [PMID: 19631512
    [Google Scholar]
  131. Xia D. Zhang Y.T. Xu G.P. Yan W.W. Pan X.R. Tong J.H. Sertraline exerts its antitumor functions through both apoptosis and autophagy pathways in acute myeloid leukemia cells. Leuk. Lymphoma 2017 58 9 1 10 [PMID: 28278721
    [Google Scholar]
  132. Reddy K.K. Lefkove B. Chen L.B. Govindarajan B. Carracedo A. Velasco G. Carrillo C.O. Bhandarkar S.S. Owens M.J. Mechta-Grigoriou F. Arbiser J.L. The antidepressant sertraline downregulates Akt and has activity against melanoma cells. Pigment Cell Melanoma Res. 2008 21 4 451 456 [PMID: 18710373
    [Google Scholar]
  133. Boia-Ferreira M. Basílio A.B. Hamasaki A.E. Matsubara F.H. Appel M.H. Da Costa C.R.V. Amson R. Telerman A. Chaim O.M. Veiga S.S. Senff-Ribeiro A. TCTP as a therapeutic target in melanoma treatment. Br. J. Cancer 2017 117 5 656 665 [PMID: 28751755
    [Google Scholar]
  134. Chinnapaka S. Bakthavachalam V. Munirathinam G. Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance. Am. J. Cancer Res. 2020 10 7 2043 2065 [PMID: 32775000
    [Google Scholar]
  135. Huang J.K. Chang H.T. Chou C.T. Shu S.S. Kuo C.C. Tsai J.Y. Liao W.C. Wang J.L. Lin K.L. Lu Y.C. Chen I.S. Liu S.I. Ho C.M. Jan C.R. The mechanism of sertraline-induced [Ca(2+)](i) rise in human PC3 prostate cancer cells. Basic Clin. Pharmacol. Toxicol. 2011 109 2 103 110 10.1111/j.1742‑7843.2011.00690.x 21371263
    [Google Scholar]
  136. Chien J.M. Chou C.T. Pan C.C. Kuo C.C. Tsai J.Y. Liao W.C. Kuo D.H. Shieh P. Ho C.M. Chu S.T. Su H.H. Chi C.C. Jan C.R. The mechanism of sertraline-induced [Ca2+]i rise in human OC2 oral cancer cells. Hum. Exp. Toxicol. 2011 30 10 1635 1643 10.1177/0960327110396523 21247994
    [Google Scholar]
  137. Lin K.L. Chi C.C. Lu T. Tseng L.L. Wang J.L. Lu Y.C. Jan C.R. Effect of sertraline on [Ca2+](i) and viability of human MG63 osteosarcoma cells. Drug Chem. Toxicol. 2013 36 2 231 240 10.3109/01480545.2012.710625 22931138
    [Google Scholar]
  138. Mu C. Peng R.K. Guo C.L. Li A. Yang X.M. Zeng R. Li Y.L. Gu J. Ouyang Q. Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis. Bioorg. Med. Chem. Lett. 2021 41 127997 [PMID: 33775839
    [Google Scholar]
  139. Wang K. Gong Q. Zhan Y. Chen B. Yin T. Lu Y. Zhang Y. Wang H. Ke J. Du B. Liu X. Xiao J. Blockage of autophagic flux and induction of mitochondria fragmentation by paroxetine hydrochloride in lung cancer cells promotes apoptosis via the ROS-MAPK pathway. Front. Cell Dev. Biol. 2020 7 397 10.3389/fcell.2019.00397 32039209
    [Google Scholar]
  140. Jang W.J. Jung S.K. Vo T.T.L. Jeong C.H. Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3. J. Cell. Mol. Med. 2019 23 2 1106 1115 10.1111/jcmm.14011 30421568
    [Google Scholar]
  141. Cho Y.W. Kim E.J. Nyiramana M.M. Shin E.J. Jin H. Ryu J.H. Kang K.R. Lee G.W. Kim H.J. Han J. Kang D. Paroxetine induces apoptosis of human breast cancer MCF-7 cells through Ca2+-and p38 MAP kinase-dependent ROS generation. Cancers 2019 11 1 64 10.3390/cancers11010064 30634506
    [Google Scholar]
  142. Xia Z. Bergstrand A. DePierre J.W. Nässberger L. The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J. Biochem. Mol. Toxicol. 1999 13 6 338 347 10.1002/(SICI)1099‑0461(1999)13:6<338:AID‑JBT8>3.0.CO;2‑7 10487422
    [Google Scholar]
  143. Chou C.T. He S. Jan C.R. Paroxetine-induced apoptosis in human osteosarcoma cells: Activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. Toxicol. Appl. Pharmacol. 2007 218 3 265 273 10.1016/j.taap.2006.11.012 17174998
    [Google Scholar]
  144. Liu B.H. Yuan T.M. Huang C.J. Hsu D.T. Chen S.W. Hsiao N.W. Lin S.C. Wu S.W. Lin Y.J. Chuang S.M. DNA repair proteins as the targets for paroxetine to induce cytotoxicity in gastric cancer cell AGS. Am. J. Cancer Res. 2022 12 4 1465 1483 [PMID: 35530295
    [Google Scholar]
  145. Yuan I. Horng C.T. Chen V.C. Chen C.H. Chen L.J. Hsu T.C. Tzang B.S. Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. Oncol. Lett. 2018 15 3 3376 3382 [PMID: 29435082
    [Google Scholar]
  146. Chen V.C.H. Hsieh Y.H. Chen L.J. Hsu T.C. Tzang B.S. Escitalopram oxalate induces apoptosis in U‐87 MG cells and autophagy in GBM 8401 cells. J. Cell. Mol. Med. 2018 22 2 1167 1178 10.1111/jcmm.13372 29105282
    [Google Scholar]
  147. Iskar M. Bork P. van Noort V. Discovery and validation of the antimetastatic activity of citalopram in colorectal cancer. Mol. Cell. Oncol. 2015 2 2 e975080 10.4161/23723556.2014.975080 27308430
    [Google Scholar]
  148. Ahmadian E. Eftekhari A. Babaei H. Nayebi A.M. Eghbal M.A. Anti-cancer effects of citalopram on hepatocellular carcinoma cells occur via cytochrome C release and the activation of NF-kB. Anticancer. Agents Med. Chem. 2017 17 11 1570 1577 [PMID: 28356024
    [Google Scholar]
  149. Sakka L. Delétage N. Chalus M. Aissouni Y. Sylvain-Vidal V. Gobron S. Coll G. Assessment of citalopram and escitalopram on neuroblastoma cell lines: Cell toxicity and gene modulation. Oncotarget 2017 8 26 42789 42807 10.18632/oncotarget.17050 28467792
    [Google Scholar]
  150. Hayashi K. Michiue H. Yamada H. Takata K. Nakayama H. Wei F.Y. Fujimura A. Tazawa H. Asai A. Ogo N. Miyachi H. Nishiki T. Tomizawa K. Takei K. Matsui H. Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. Sci. Rep. 2016 6 1 23372 10.1038/srep23372 26988603
    [Google Scholar]
  151. Li M. Duan L. Wu W. Li W. Zhao L. Li A. Lu X. He X. Dong Z. Liu K. Jiang Y. Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC. Oncogenesis 2023 12 1 24 10.1038/s41389‑023‑00472‑4 37147297
    [Google Scholar]
  152. Lv G.B. Wang T.T. Zhu H.L. Wang H.K. Sun W. Zhao L.F. Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway. FEBS Open Bio 2020 10 10 2157 2165 10.1002/2211‑5463.12944 32750222
    [Google Scholar]
  153. Devare M.N. Kaeberlein M. An anti-depressant drug vortioxetine suppresses malignant glioblastoma cell growth. MicroPubl Biol 2024 10.1101/2024.03.04.583265
    [Google Scholar]
  154. Zhang H.Q. Zhang D.M. Huang Z.Z. Cheng J. Zhang C. Lin N.M. Li Y. Vortioxetine exhibits anti-glioblastoma activity via the PI3K-Akt signaling pathway. Iran. J. Basic Med. Sci. 2025 28 4 401 408 [PMID: 39968089
    [Google Scholar]
  155. Zhou T. Duan J. Wang Y. Chen X. Zhou G. Wang R. Fu L. Xu F. Fluoxetine synergys with anticancer drugs to overcome multidrug resistance in breast cancer cells. Tumour Biol. 2012 33 5 1299 1306 10.1007/s13277‑012‑0377‑4 22549660
    [Google Scholar]
  156. Liu Y. Fluoxetine enhances cellular chemosensitivity to cisplatin in cervical cancer. Int. J. Clin. Exp. Med. 2017 10 10521 10527
    [Google Scholar]
  157. Argov M. Kashi R. Peer D. Margalit R. Treatment of resistant human colon cancer xenografts by a fluoxetine–doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett. 2009 274 1 118 125 10.1016/j.canlet.2008.09.005 18851896
    [Google Scholar]
  158. Engelmann B.J. Ryan J.J. Farrell N.P. Antidepressants and platinum drugs. Anticancer Res. 2014 34 1 509 516 [PMID: 24403509
    [Google Scholar]
  159. Khing T.M. Po W.W. Sohn U.D. Fluoxetine Enhances Anti-tumor Activity of Paclitaxel in Gastric Adenocarcinoma Cells by Triggering Apoptosis and Necroptosis. Anticancer Res. 2019 39 11 6155 6163 10.21873/anticanres.13823 31704843
    [Google Scholar]
  160. Ma J. Yang Y.R. Chen W. Chen M.H. Wang H. Wang X.D. Sun L.L. Wang F.Z. Wang D.C. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncol. Rep. 2016 36 2 676 684 10.3892/or.2016.4860 27278525
    [Google Scholar]
  161. Bin Kanner Y. Teng Q.X. Ganoth A. Peer D. Wang J.Q. Chen Z.S. Tsfadia Y. Cytotoxicity and reversal effect of sertraline, fluoxetine, and citalopram on MRP1- and MRP7-mediated MDR. Front. Pharmacol. 2023 14 1290255 10.3389/fphar.2023.1290255 38026953
    [Google Scholar]
  162. Tzadok S. Beery E. Israeli M. Uziel O. Lahav M. Fenig E. Gil-Ad I. Weizman A. Nordenberg J. In vitro novel combinations of psychotropics and anti-cancer modalities in U87 human glioblastoma cells. Int. J. Oncol. 2010 37 4 1043 1051 10.3892/ijo_00000756 20811727
    [Google Scholar]
  163. Duarte D. Falcão S.I. El Mehdi I. Vilas-Boas M. Vale N. Honeybee venom synergistically enhances the cytotoxic effect of CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. Pharmaceutics 2022 14 3 511 10.3390/pharmaceutics14030511 35335887
    [Google Scholar]
  164. Hallett R.M. Girgis-Gabardo A. Gwynne W.D. Giacomelli A.O. Bisson J.N.P. Jensen J.E. Dvorkin-Gheva A. Hassell J.A. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer. Oncotarget 2016 7 33 53137 53152 10.18632/oncotarget.10614 27447971
    [Google Scholar]
  165. Geeraerts S.L. Kampen K.R. Rinaldi G. Gupta P. Planque M. Louros N. Heylen E. De Cremer K. De Brucker K. Vereecke S. Verbelen B. Vermeersch P. Schymkowitz J. Rousseau F. Cassiman D. Fendt S.M. Voet A. Cammue B.P.A. Thevissen K. De Keersmaecker K. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis–addicted breast tumor growth. Mol. Cancer Ther. 2021 20 1 50 63 10.1158/1535‑7163.MCT‑20‑0480 33203732
    [Google Scholar]
  166. Drinberg V. Bitcover R. Rajchenbach W. Peer D. Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine. Cancer Lett. 2014 354 2 290 298 10.1016/j.canlet.2014.08.026 25173796
    [Google Scholar]
  167. Zhang H. Chen M. Liu Y. Dong X. Zhang C. Jiang H. Chen X. Paroxetine combined with fluorouracil plays a therapeutic role in mouse models of colorectal cancer with depression through inhibiting IL 22 expression to regulate the MAPK signaling pathway. Exp. Ther. Med. 2020 20 6 1 10.3892/etm.2020.9370 33178338
    [Google Scholar]
  168. Ion G.N.D. Nitulescu G.M. Popescu C.I. Targeting TRAIL. Bioorg. Med. Chem. Lett. 2019 29 18 2527 2534 10.1016/j.bmcl.2019.07.053 31383590
    [Google Scholar]
  169. Sabapathy K. Lane D.P. Understanding p53 functions through p53 antibodies. J. Mol. Cell Biol. 2019 11 4 317 329 10.1093/jmcb/mjz010 30907951
    [Google Scholar]
  170. Tuynder M. Fiucci G. Prieur S. Lespagnol A. Géant A. Beaucourt S. Duflaut D. Besse S. Susini L. Cavarelli J. Moras D. Amson R. Telerman A. Translationally controlled tumor protein is a target of tumor reversion. Proc. Natl. Acad. Sci. USA 2004 101 43 15364 15369 10.1073/pnas.0406776101 15489264
    [Google Scholar]
  171. Amson R. Karp J.E. Telerman A. Lessons from tumor reversion for cancer treatment. Curr. Opin. Oncol. 2013 25 1 59 65 10.1097/CCO.0b013e32835b7d21 23165143
    [Google Scholar]
  172. Wirsching H.G. Galanis E. Weller M. Glioblastoma. Handb. Clin. Neurol. 2016 134 381 397 10.1016/B978‑0‑12‑802997‑8.00023‑2 26948367
    [Google Scholar]
  173. Pollard T.D. Borisy G.G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003 112 4 453 465 10.1016/S0092‑8674(03)00120‑X 12600310
    [Google Scholar]
  174. Nürnberg A. Kitzing T. Grosse R. Nucleating actin for invasion. Nat. Rev. Cancer 2011 11 3 177 187 10.1038/nrc3003 21326322
    [Google Scholar]
  175. Duarte D. Rêma A. Amorim I. Vale N. Drug combinations: A new strategy to extend drug repurposing and epithelial-mesenchymal transition in breast and colon cancer cells. Biomolecules 2022 12 2 190 10.3390/biom12020190 35204691
    [Google Scholar]
  176. Stapel B. Melzer C. von der Ohe J. Hillemanns P. Bleich S. Kahl K.G. Hass R. Effect of SSRI exposure on the proliferation rate and glucose uptake in breast and ovary cancer cell lines. Sci. Rep. 2021 11 1 1250 10.1038/s41598‑020‑80850‑9 33441923
    [Google Scholar]
  177. Jia L. Shang Y.Y. Li Y.Y. Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice. World J. Gastroenterol. 2008 14 27 4377 4382 [PMID: 18666329
    [Google Scholar]
  178. Bendele R.A. Adams E.R. Hoffman W.P. Gries C.L. Morton D.M. Carcinogenicity studies of fluoxetine hydrochloride in rats and mice. Cancer Res. 1992 52 24 6931 6935 [PMID: 1458482
    [Google Scholar]
  179. Kubera M. Grygier B. Arteta B. Urbańska K. Basta-Kaim A. Budziszewska B. Leśkiewicz M. Kołaczkowska E. Maes M. Szczepanik M. Majewska M. Lasoń W. Age-dependent stimulatory effect of desipramine and fluoxetine pretreatment on metastasis formation by B16F10 melanoma in male C57BL/6 mice. Pharmacol. Rep. 2009 61 6 1113 1126 10.1016/S1734‑1140(09)70174‑4 20081247
    [Google Scholar]
  180. Kubera M. Grygier B. Wrona D. Rogóż Z. Roman A. Basta-Kaim A. Budziszewska B. Leskiewicz M. Jantas D. Nowak W. Maes M. Lason W. Stimulatory effect of antidepressant drug pretreatment on progression of B16F10 melanoma in high-active male and female C57BL/6J mice. J. Neuroimmunol. 2011 240-241 34 44 10.1016/j.jneuroim.2011.09.006 22030244
    [Google Scholar]
/content/journals/ccdt/10.2174/0115680096372733250611114329
Loading
An Overview of the Potential Use of Selective Serotonin Reuptake Inhibitors (SSRIs) in Cancer Treatment
Bentham Science Publishers ; https://doi.org/10.2174/0115680096372733250611114329
/content/journals/ccdt/10.2174/0115680096372733250611114329
/content/journals/ccdt/10.2174/0115680096372733250611114329
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Review Article
Keywords: SSRIs ; drug repurposing ; network pharmacology ; monotherapy ; combination therapy ; Cancer treatment

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test