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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Antidepressant Sertraline Hydrochloride Inhibits the Growth of HER2+ AU565 Breast Cancer Cell Line through Induction of Apoptosis and Cell Cycle Arrest

Author(s): Sharmeen Fayyaz, Atia-Tul-Wahab*, Rimsha Irshad, Rafat A. Siddiqui and M. Iqbal Choudhary*

Volume 24, Issue 14, 2024

Published on: 17 May, 2024

Page: [1038 - 1046] Pages: 9

DOI: 10.2174/0118715206304918240509111700

Price: $65

Abstract

Background: Drug repurposing in oncology promises benefits to many patients through its ability to provide novel, and fast-tracked treatments. Previous studies have demonstrated that depression may influence tumor progression. Anti-proliferative activity of certain antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), are reported in the literature.

Objective: This study was conducted to repurpose selective serotonin reuptake inhibitors (SSRIs) for the treatment of breast cancers, and it merits further validation and research.

Methods: Changes in cell morphology were studied using DAPI staining, while the Annexin V/PI method was employed for apoptotic analysis. The expression of specific genes involved in cancer progression was also analyzed via RT-PCR. Caspase-3 activation was measured through fluorometric assay.

Results: We have identified that sertraline hydrochloride significantly inhibited the growth of breast cancer cell in vitro. Preliminary mechanistic studies demonstrated that the cytotoxicity of sertraline hydrochloride was possibly through the induction of apoptosis, as inferred from enhanced nuclear fragmentation, flow cytometric data, and caspase-3/7 activation. Gene expression analysis also showed an increased expression of pro-apoptotic Bax, and a slight decrease in oncogene c-myc in the presence of sertraline hydrochloride.

Conclusion: In conclusion, our study suggest that sertraline hydrochloride, an antidepressant drug, can potentially be used for the treatment of breast cancer.

Keywords: Sertraline hydrochloride, breast cancer, drug repurposing, selective serotonin reuptake inhibitors, apoptosis, c-myc.

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[1]
Chang, L.; Weiner, L.S.; Hartman, S.J.; Horvath, S.; Jeste, D.; Mischel, P.S.; Kado, D.M. Breast cancer treatment and its effects on aging. J. Geriatr. Oncol., 2019, 10(2), 346-355.
[http://dx.doi.org/10.1016/j.jgo.2018.07.010] [PMID: 30078714]
[2]
Tate, C.R.; Rhodes, L.V.; Segar, H.C.; Driver, J.L.; Pounder, F.N.; Burow, M.E.; Collins-Burow, B.M. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res., 2012, 14(3), R79.
[http://dx.doi.org/10.1186/bcr3192] [PMID: 22613095]
[3]
Soomro, R.; Faridi, S.; Khurshaidi, N.; Zahid, N.; Mamshad, I. Age and stage of breast cancer in Pakistan: An experience at a tertiary care center. J. Pak. Med. Assoc., 2018, 68(11), 1682-1685.
[PMID: 30410149]
[4]
Zahid, I.; Ahmed, A.; Ladiwala, Z.F.; Sheikh, R.; Memon, A. Breast self-examination awareness and practices in young women in developing countries: A survey of female students in Karachi, Pakistan. J. Educ. Health Promot., 2018, 7(1), 90.
[http://dx.doi.org/10.4103/jehp.jehp_147_17] [PMID: 30079361]
[5]
Badran, A. Atia-tul-Wahab; Fayyaz, S.; Baydoun, E.; Choudhary, M.I. Small molecular leads differentially active against HER2 positive and triple negative breast cancer cell lines. Med. Chem., 2019, 15(7), 738-742.
[http://dx.doi.org/10.2174/1573406414666181106143912] [PMID: 30398120]
[6]
Das, J.R.; Fryar-Tita, E.B.; Zhou, Y.; Green, S.; Southerland, W.M.; Bowen, D. Sequence-dependent administration of 5-fluorouracil maintains methotrexate antineoplastic activity in human estrogen-negative breast cancer and protects against methotrexate cytotoxicity in human bone marrow. Anticancer Res., 2007, 27(6B), 3791-3799.
[PMID: 18225534]
[7]
Gombos, A.; Franzoi, M.A.; Awada, A. Investigational drugs in early stage clinical trials for the treatment of HER2+ breast cancer. Exp. Opin. Inv. Drug., 2019, 28(7), 617-627.
[8]
Grassi, L.; Nanni, M.G.; Rodin, G.; Li, M.; Caruso, R. The use of antidepressants in oncology: A review and practical tips for oncologists. Ann. Oncol., 2018, 29(1), 101-111.
[http://dx.doi.org/10.1093/annonc/mdx526] [PMID: 29272358]
[9]
Han, H.; Guo, W.; Shi, W.; Yu, Y.; Zhang, Y.; Ye, X.; He, J. Hypertension and breast cancer risk: A systematic review and meta-analysis. Sci. Rep., 2017, 7(1), 44877.
[http://dx.doi.org/10.1038/srep44877] [PMID: 28317900]
[10]
Lieb, J. Defeating cancer with antidepressants. Ecancermedicalscience, 2008, 2, 88.
[PMID: 22275973]
[11]
Hinz, A.; Krauss, O.; Hauss, J.P.; Höckel, M.; Kortmann, R.D.; Stolzenburg, J.U.; Schwarz, R. Anxiety and depression in cancer patients compared with the general population. Eur. J. Cancer Care (Engl.), 2010, 19(4), 522-529.
[http://dx.doi.org/10.1111/j.1365-2354.2009.01088.x] [PMID: 20030697]
[12]
Balentine, C.J.; Hermosillo-Rodriguez, J.; Robinson, C.N.; Berger, D.H.; Naik, A.D. Depression is associated with prolonged and complicated recovery following colorectal surgery. J. Gastrointest. Surg., 2011, 15(10), 1712.
[13]
Narayanan, V. Ocular Adverse effects of antidepressants–need for an ophthalmic screening and follow up protocol. O.Res. An. Int. J., 2019, 20, 1-6.
[http://dx.doi.org/10.9734/or/2019/v10i330107]
[14]
Haskell, S.E.; Hermann, G.M.; Reinking, B.E.; Volk, K.A.; Peotta, V.A.; Zhu, V.; Roghair, R.D. Sertraline exposure leads to small left heart syndrome in adult mice. Pediatr. Res., 2013, 73(3), 286-293.
[http://dx.doi.org/10.1038/pr.2012.183] [PMID: 23232669]
[15]
Kotapati, V.P.; Khan, A.M.; Dar, S.; Begum, G.; Bachu, R.; Adnan, M.; Zubair, A.; Ahmed, R.A. The effectiveness of selective serotonin reuptake inhibitors for treatment of obsessive-compulsive disorder in adolescents and children: A systematic review and meta-analysis. Front. Psychiatry, 2019, 10, 523.
[http://dx.doi.org/10.3389/fpsyt.2019.00523] [PMID: 31447707]
[16]
Patel, R. Anti-proliferative effects of selected antidepressant agents on human metastatic breast cancer cell line, MDA-MB-231., Doctoral dissertation, Long Island University, The Brooklyn Center., 2013.
[17]
Zong, D.; Zielinska-Chomej, K.; Juntti, T.; Mörk, B.; Lewensohn, R.; Hååg, P.; Viktorsson, K. Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer. Cell Death Dis., 2014, 5(3), e1111.
[http://dx.doi.org/10.1038/cddis.2014.56] [PMID: 24625970]
[18]
Goyette, M.A.; Cusseddu, R.; Elkholi, I.; Abu-Thuraia, A.; El-Hachem, N.; Haibe-Kains, B.; Gratton, J.P.; Côté, J.F. AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer. Oncotarget, 2019, 10(21), 2055-2067.
[http://dx.doi.org/10.18632/oncotarget.26725] [PMID: 31007848]
[19]
Rosetti, M.; Frasnelli, M.; Tesei, A.; Zoli, W.; Conti, M. Cytotoxicity of different selective serotonin reuptake inhibitors (SSRIs) against cancer cells. J. Exp. Ther. Oncol., 2006, 6(1), 23-29.
[PMID: 17228521]
[20]
Abdel Karim, N.F.; Hassan, R.; Siddiqi, N.I.; Eldessouki, I.; Gaber, O.; Rahouma, M.; Kamel, M.; Yellu, M.; Gulati, S.; Xie, C.; Magdy, M.; Pruemer, J. Impact of tricyclic antidepressants, selective serotonin reuptake inhibitors, and other antidepressants on overall survival of patients with advanced lung cancer from 2004 to 2014: University of Cincinnati experience. J. Int. Med. Res., 2019, 47(12), 6016-6026.
[http://dx.doi.org/10.1177/0300060519862469] [PMID: 31640444]
[21]
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.
[http://dx.doi.org/10.1182/blood-2002-07-2044] [PMID: 12515726]
[22]
Gwynne, W.D.; Shakeel, M.S.; Girgis-Gabardo, A.; Hassell, J.A. The role of serotonin in breast cancer stem cells. Molecules, 2021, 26(11), 3171.
[http://dx.doi.org/10.3390/molecules26113171] [PMID: 34073226]
[23]
Duarte, D.; Vale, N. Antidepressant drug sertraline against human cancer cells. Biomolecules, 2022, 12(10), 1513.
[http://dx.doi.org/10.3390/biom12101513] [PMID: 36291722]
[24]
Taler, M.; Gil-Ad, I.; Brener, I.; Hornfeld, S.H.; Weizman, A. Complex effects of sertraline and citalopram on in vitro murine breast cancer proliferation and on in vivo progression and anxiety level. Int. J. Mol. Sci., 2022, 23(5), 2711.
[http://dx.doi.org/10.3390/ijms23052711] [PMID: 35269853]
[25]
Bar-Shalom, R.; Bergman, M.; Grossman, S.; Azzam, N.; Sharvit, L.; Fares, F. Inula viscosa extract inhibits growth of colorectal cancer cells in vitro and in vivo through induction of apoptosis. Front. Oncol., 2019, 9, 227.
[http://dx.doi.org/10.3389/fonc.2019.00227] [PMID: 31024836]
[26]
Sturzu, A.; Sheikh, S.; Echner, H.; Deeg, M.; Nägele, T.; Weidenmaier, C.; Schwentner, C.; Horger, M.; Ernemann, U.; Heckl, S. Chemosensitization of prostate carcinoma cells with a receptor-directed Smac conjugate. Med. Chem., 2016, 12(5), 412-418.
[http://dx.doi.org/10.2174/1573406412666151112125622] [PMID: 26558373]
[27]
Hanbashi, A. Anti-proliferative mechanism of selective serotonin re-uptake inhibitor sertraline on human metastatic breast cancer cell line MCF7. Doctoral dissertation, Long Island University, The Brooklyn Center, 2014.
[28]
Budajaja, F. Anti-proliferative mechanism of selective serotonin reuptakeinhibitor– sertraline-on human metastatic breast cancer cell line, MDA-MB-231. Doctoral dissertation, Long Island University, The Brooklyn Center, 2014.
[29]
Sunilkumar, D.; Drishya, G.; Chandrasekharan, A.; Shaji, S.K.; Bose, C.; Jossart, J.; Perry, J.J.P.; Mishra, N.; Kumar, G.B.; Nair, B.G. Oxyresveratrol drives caspase-independent apoptosis-like cell death in MDA-MB-231 breast cancer cells through the induction of ROS. Biochem. Pharmacol., 2020, 173, 113724.
[http://dx.doi.org/10.1016/j.bcp.2019.113724] [PMID: 31756327]
[30]
Wen, Y.; Zhang, Y.; Li, J.; Luo, F.; Huang, Z.; Liu, K. Low concentration trifluoperazine promotes proliferation and reduces calcium-dependent apoptosis in glioma cells. Sci. Rep., 2018, 8(1), 1147.
[http://dx.doi.org/10.1038/s41598-018-19413-y] [PMID: 29348654]
[31]
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.
[http://dx.doi.org/10.1038/srep23372] [PMID: 26988603]
[32]
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.
[http://dx.doi.org/10.1038/s41598-020-80850-9] [PMID: 33441923]
[33]
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.
[http://dx.doi.org/10.3390/ijms22147408] [PMID: 34299028]
[34]
Duarte, D.; Nunes, M.; Ricardo, S.; Vale, N. Combination of antimalarial and CNS drugs with antineoplastic agents in MCF-7 breast and HT-29 colon cancer cells: Biosafety evaluation and mechanism of action. Biomolecules, 2022, 12(10), 1490.
[http://dx.doi.org/10.3390/biom12101490] [PMID: 36291699]
[35]
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.
[http://dx.doi.org/10.1093/toxsci/kft254] [PMID: 24194395]
[36]
Hodge, J.M.; Wang, Y.; Berk, M.; Collier, F.M.; Fernandes, T.J.; Constable, M.J.; Pasco, J.A.; Dodd, S.; Nicholson, G.C.; Kennedy, R.L.; Williams, L.J. Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function. Biol. Psychiatry, 2013, 74(1), 32-39.
[http://dx.doi.org/10.1016/j.biopsych.2012.11.003] [PMID: 23260229]
[37]
Atli, O.; Baysal, M.; Aydogan-Kilic, G.; Kilic, V.; Ucarcan, S.; Karaduman, B.; Ilgin, S. Sertraline-induced reproductive toxicity in male rats: Evaluation of possible underlying mechanisms. Asian J. Androl., 2017, 19(6), 672-679.
[http://dx.doi.org/10.4103/1008-682X.192637] [PMID: 27976631]
[38]
Erdemir, F.; Atilgan, D.; Firat, F.; Markoc, F.; Parlaktas, B.S.; Sogut, E. The effect of Sertraline, Paroxetine, Fluoxetine and Escitalopram on testicular tissue and oxidative stress parameters in rats. Int. Braz J Urol, 2014, 40(1), 100-108.
[http://dx.doi.org/10.1590/S1677-5538.IBJU.2014.01.15] [PMID: 24642156]
[39]
Tanrikut, C.; Feldman, AS.; Altemus, M.; Paduch, DA.; Schlegel, PN. Adverse effect of paroxetine on sperm. Fertil. Steril., 2010, 94(3), 1021-1026.
[http://dx.doi.org/10.1016/j.fertnstert.2009.04.039]
[40]
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]
[41]
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), 2208-2217.
[http://dx.doi.org/10.1080/10428194.2017.1287358] [PMID: 28278721]
[42]
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.
[http://dx.doi.org/10.1158/1535-7163.MCT-20-0480] [PMID: 33203732]
[43]
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.
[http://dx.doi.org/10.1016/j.bcp.2008.02.013] [PMID: 18371935]
[44]
Li, Y.; Couch, L.; Higuchi, M.; Fang, J.L.; Guo, L. Mitochondrial dysfunction induced by sertraline, an antidepressant agent. Toxicol. Sci., 2012, 127(2), 582-591.
[http://dx.doi.org/10.1093/toxsci/kfs100] [PMID: 22387747]
[45]
Then, C.K.; Liu, K.H.; Liao, M.H.; Chung, K.H.; Wang, J.Y.; Shen, S.C. Antidepressants, sertraline and paroxetine, increase calcium influx and induce mitochondrial damage-mediated apoptosis of astrocytes. Oncotarget, 2017, 8(70), 115490-115502.
[http://dx.doi.org/10.18632/oncotarget.23302] [PMID: 29383176]
[46]
Achenbach, T.V.; Müller, R.; Slater, E.P. Bcl-2 independence of flavopiridol-induced apoptosis. Mitochondrial depolarization in the absence of cytochrome c release. J. Biol. Chem., 2000, 275(41), 32089-32097.
[http://dx.doi.org/10.1074/jbc.M005267200] [PMID: 10896673]
[47]
Duarte, D.; Guerreiro, I.; Vale, N. Novel strategies for cancer combat: Drug combination using repurposed drugs induces synergistic growth inhibition of MCF-7 breast and HT-29 colon cancer cells. Curr. Issues Mol. Biol., 2022, 44(10), 4930-4949.
[http://dx.doi.org/10.3390/cimb44100335] [PMID: 36286050]
[48]
Baldissera, A.B.; Boia-Ferreira, M.; Basílio, A.B.C.; Resende, J.S.S.; Castro, M.A.A.; Chaim, O.M.; Gremski, L.H.; Veiga, S.S.; Senff-Ribeiro, A. Sertraline as a potential cancer therapeutic approach: Biological relevance of TCTP in breast cancer cell lines and tumors. Adv. Med. Sci., 2023, 68(2), 227-237.
[http://dx.doi.org/10.1016/j.advms.2023.06.001] [PMID: 37379765]

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