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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Novel STAT3 Inhibitor Exerts Anti-breast Cancer Effects Both In vitro and In vivo

Author(s): Zhe Liu, Yiming Sun, Meiling Yu, Yingying Huang, Liang Ma* and Lingti Kong*

Volume 20, Issue 12, 2023

Published on: 03 February, 2023

Page: [2070 - 2079] Pages: 10

DOI: 10.2174/1570180820666230116153822

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Abstract

Background: Breast cancer is one of the most common malignant tumors. Signal transduction and activators of transcription 3 (STAT3) have been demonstrated to play important roles in breast cancer. However, no direct inhibitor of STAT3 has been approved by the FDA for clinical use.

Objective: LL1 is a newly designed STAT3 inhibitor that we identified. In this study, we investigated the cytotoxic effect of LL1 on breast cancer cells and its potential mechanisms.

Methods: Colony formation and CCK-8 assay were used to detect the anti-proliferation of LL1. Flow cytometry was used to evaluate mitochondrial membrane potential and apoptosis in breast cancer cells following the treatment of LL1. The expression of proteins was analyzed using western blot, and the invasion and migration of cells were analyzed by wound healing assay and transwell assay. The xenograft model was used to evaluate the anti-cancer effect of LL1 in vivo.

Results: LL1 selectively inhibited the expression of p-STAT3, but had no obvious effect on total STAT3. LL1 exhibited great potential in suppressing the proliferation of breast cancer in vitro. Moreover, LL1 induces apoptosis and the decrease of mitochondrial membrane potential in breast cancer cells. LL1 can also inhibit the invasion and migration of breast cancer cells. These cell biology changes may be induced via the regulation of Bcl-2, Bax, cleaved-caspase3, Survivn, Mmp-2, Mmp-9, N-cadherin, E-cadherin, vimentin, c-myc and cyclin D1 by LL1. In addition, LL1 exhibited great antitumor activity in vivo.

Conclusion: Our study suggested that LL1 can be considered a promising candidate for the treatment of breast cancer.

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[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Wright, T.; McGechan, A. Breast cancer: new technologies for risk assessment and diagnosis. Mol. Diagn., 2003, 7(1), 49-55.
[PMID: 14529321]
[3]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin., 2022, 72(1), 7-33.
[http://dx.doi.org/10.3322/caac.21708] [PMID: 35020204]
[4]
Trayes, K.P.; Cokenakes, S.E.H. Breast cancer treatment. Am. Fam. Physician, 2021, 104(2), 171-178.
[PMID: 34383430]
[5]
O’Shea, J.J.; Holland, S.M.; Staudt, L.M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med., 2013, 368(2), 161-170.
[http://dx.doi.org/10.1056/NEJMra1202117] [PMID: 23301733]
[6]
Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer, 2009, 9(11), 798-809.
[http://dx.doi.org/10.1038/nrc2734] [PMID: 19851315]
[7]
Kumari, N.; Dwarakanath, B.S.; Das, A.; Bhatt, A.N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol., 2016, 37(9), 11553-11572.
[http://dx.doi.org/10.1007/s13277-016-5098-7] [PMID: 27260630]
[8]
Furtek, S.L.; Backos, D.S.; Matheson, C.J.; Reigan, P. Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem. Biol., 2016, 11(2), 308-318.
[http://dx.doi.org/10.1021/acschembio.5b00945] [PMID: 26730496]
[9]
Banerjee, K.; Resat, H. Constitutive activation of STAT3 in breast cancer cells: A review. Int. J. Cancer, 2016, 138(11), 2570-2578.
[http://dx.doi.org/10.1002/ijc.29923] [PMID: 26559373]
[10]
Kamran, M.Z.; Patil, P.; Gude, R.P. Role of STAT3 in cancer metastasis and translational advances. BioMed Res. Int., 2013, 2013, 1-15.
[http://dx.doi.org/10.1155/2013/421821] [PMID: 24199193]
[11]
Wake, M.S.; Watson, C.J. STAT3 the oncogene-Still eluding therapy? FEBS J., 2015, 282(14), 2600-2611.
[http://dx.doi.org/10.1111/febs.13285] [PMID: 25825152]
[12]
Bar-Natan, M.; Nelson, E.A.; Xiang, M.; Frank, D.A. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAK-STAT, 2012, 1(2), 55-64.
[http://dx.doi.org/10.4161/jkst.20006] [PMID: 24058751]
[13]
Diaz, N.; Minton, S.; Cox, C.; Bowman, T.; Gritsko, T.; Garcia, R.; Eweis, I.; Wloch, M.; Livingston, S.; Seijo, E.; Cantor, A.; Lee, J.H.; Beam, C.A.; Sullivan, D.; Jove, R.; Muro-Cacho, C.A. Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin. Cancer Res., 2006, 12(1), 20-28.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1749] [PMID: 16397019]
[14]
Gritsko, T.; Williams, A.; Turkson, J.; Kaneko, S.; Bowman, T.; Huang, M.; Nam, S.; Eweis, I.; Diaz, N.; Sullivan, D.; Yoder, S.; Enkemann, S.; Eschrich, S.; Lee, J.H.; Beam, C.A.; Cheng, J.; Minton, S.; Muro-Cacho, C.A.; Jove, R. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res., 2006, 12(1), 11-19.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1752] [PMID: 16397018]
[15]
Liu, Z.; Ma, L.; Sun, Y.; Yu, W.; Wang, X. Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer. Cell Death Dis., 2021, 12(6), 561.
[http://dx.doi.org/10.1038/s41419-021-03844-z] [PMID: 34059647]
[16]
Siersbæk, R.; Scabia, V.; Nagarajan, S.; Chernukhin, I.; Papachristou, E.K.; Broome, R.; Johnston, S.J.; Joosten, S.E.P.; Green, A.R.; Kumar, S.; Jones, J.; Omarjee, S.; Alvarez-Fernandez, R.; Glont, S.; Aitken, S.J.; Kishore, K.; Cheeseman, D.; Rakha, E.A.; D’Santos, C.; Zwart, W.; Russell, A.; Brisken, C.; Carroll, J.S. IL6/STAT3 signaling hijacks estrogen receptor α enhancers to drive breast cancer metastasis. Cancer Cell, 2020, 38(3), 412-423.e9.
[http://dx.doi.org/10.1016/j.ccell.2020.06.007] [PMID: 32679107]
[17]
Ma, J.; Qin, L.; Li, X. Role of STAT3 signaling pathway in breast cancer. Cell Commun. Signal., 2020, 18(1), 33.
[http://dx.doi.org/10.1186/s12964-020-0527-z] [PMID: 32111215]
[18]
Song, H.; Wang, R.; Wang, S.; Lin, J. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc. Natl. Acad. Sci. USA, 2005, 102(13), 4700-4705.
[http://dx.doi.org/10.1073/pnas.0409894102] [PMID: 15781862]
[19]
Yu, H.; Lee, H.; Herrmann, A.; Buettner, R.; Jove, R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer, 2014, 14(11), 736-746.
[http://dx.doi.org/10.1038/nrc3818] [PMID: 25342631]
[20]
Dechow, T.N.; Pedranzini, L.; Leitch, A.; Leslie, K.; Gerald, W.L.; Linkov, I.; Bromberg, J.F. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc. Natl. Acad. Sci. USA, 2004, 101(29), 10602-10607.
[http://dx.doi.org/10.1073/pnas.0404100101] [PMID: 15249664]
[21]
Pan, Y.M.; Wang, C.G.; Zhu, M.; Xing, R.; Cui, J.T.; Li, W.M.; Yu, D.D.; Wang, S.B.; Zhu, W.; Ye, Y.J.; Wu, Y.; Wang, S.; Lu, Y.Y. STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. Mol. Cancer, 2016, 15(1), 79.
[http://dx.doi.org/10.1186/s12943-016-0561-z] [PMID: 27938379]
[22]
Heichler, C.; Scheibe, K.; Schmied, A.; Geppert, C.I.; Schmid, B.; Wirtz, S.; Thoma, O.M.; Kramer, V.; Waldner, M.J.; Büttner, C.; Farin, H.F.; Pešić, M.; Knieling, F.; Merkel, S.; Grüneboom, A.; Gunzer, M.; Grützmann, R.; Rose-John, S.; Koralov, S.B.; Kollias, G.; Vieth, M.; Hartmann, A.; Greten, F.R.; Neurath, M.F.; Neufert, C. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut, 2020, 69(7), 1269-1282.
[http://dx.doi.org/10.1136/gutjnl-2019-319200] [PMID: 31685519]
[23]
Tang, L.; Liu, J.X.; Zhang, Z.J.; Xu, C.Z.; Zhang, X.N.; Huang, W.R.; Zhou, D.H.; Wang, R.R.; Chen, X.D.; Xiao, M.B.; Qu, L.S.; Lu, C.H. High expression of Anxa2 and Stat3 promote progression of hepatocellular carcinoma and predict poor prognosis. Pathol. Res. Pract., 2019, 215(6), 152386.
[http://dx.doi.org/10.1016/j.prp.2019.03.015] [PMID: 30935762]
[24]
Carradori, S.; Secci, D.; De Monte, C.; Mollica, A.; Ceruso, M.; Akdemir, A.; Sobolev, A.P.; Codispoti, R.; De Cosmi, F.; Guglielmi, P.; Supuran, C.T. A novel library of saccharin and acesulfame derivatives as potent and selective inhibitors of carbonic anhydrase IX and XII isoforms. Bioorg. Med. Chem., 2016, 24(5), 1095-1105.
[http://dx.doi.org/10.1016/j.bmc.2016.01.038] [PMID: 26810710]
[25]
Mollica, A.; Costante, R.; Fiorito, S.; Genovese, S.; Stefanucci, A.; Mathieu, V.; Kiss, R.; Epifano, F. Synthesis and anti-cancer activity of naturally occurring 2,5-diketopiperazines. Fitoterapia, 2014, 98, 91-97.
[http://dx.doi.org/10.1016/j.fitote.2014.07.010] [PMID: 25064216]
[26]
Liu, Y.; Liao, S.; Bennett, S.; Tang, H.; Song, D.; Wood, D.; Zhan, X.; Xu, J. STAT3 and its targeting inhibitors in osteosarcoma. Cell Prolif., 2021, 54(2), e12974.
[http://dx.doi.org/10.1111/cpr.12974] [PMID: 33382511]
[27]
Kim, B.H.; Lee, H.; Park, C.G.; Jeong, A.J.; Lee, S.H.; Noh, K.H.; Park, J.B.; Lee, C.G.; Paek, S.H.; Kim, H.; Ye, S-K. STAT3 inhibitor ODZ10117 suppresses glioblastoma malignancy and prolongs survival in a glioblastoma xenograft model. Cells, 2020, 9(3), 722.
[http://dx.doi.org/10.3390/cells9030722]
[28]
Alexandrow, M.G.; Song, L.J.; Altiok, S.; Gray, J.; Haura, E.B.; Kumar, N.B. Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur. J. Cancer Prev., 2012, 21(5), 407-412.
[http://dx.doi.org/10.1097/CEJ.0b013e32834ef194] [PMID: 22156994]
[29]
Miklossy, G.; Hilliard, T.S.; Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov., 2013, 12(8), 611-629.
[http://dx.doi.org/10.1038/nrd4088] [PMID: 23903221]
[30]
Manaswiyoungkul, P.; Erdogan, F.; Olaoye, O.O.; Cabral, A.D.; de Araujo, E.D.; Gunning, P.T. Optimization of a high-throughput fluorescence polarization assay for STAT5B DNA binding domain-targeting inhibitors. J. Pharm. Biomed. Anal., 2020, 184, 113182.
[http://dx.doi.org/10.1016/j.jpba.2020.113182] [PMID: 32113119]
[31]
Veronesi, U.; Boyle, P.; Goldhirsch, A.; Orecchia, R.; Viale, G. Breast cancer. Lancet, 2005, 365(9472), 1727-1741.
[http://dx.doi.org/10.1016/S0140-6736(05)66546-4] [PMID: 15894099]
[32]
Vuong, D.; Simpson, P.T.; Green, B.; Cummings, M.C.; Lakhani, S.R. Molecular classification of breast cancer. Virchows Arch., 2014, 465(1), 1-14.
[http://dx.doi.org/10.1007/s00428-014-1593-7] [PMID: 24878755]
[33]
Xu, Z.; Zhang, Y.; Li, N.; Liu, P.; Gao, L.; Gao, X.; Tie, X. Efficacy and safety of lapatinib and trastuzumab for HER2-positive breast cancer: A systematic review and meta-analysis of randomised controlled trials. BMJ Open, 2017, 7(3), e013053.
[http://dx.doi.org/10.1136/bmjopen-2016-013053] [PMID: 28289045]
[34]
Dong, Y.; Xu, T.; Zhong, S.; Wang, B.; Zhang, H.; Wang, X.; Wang, P.; Li, G. Yang, S. Circ_0076305 regulates cisplatin resistance of non-small cell lung cancer via positively modulating STAT3 by sponging miR-296-5p. Life Sci., 2019, 239116984.
[35]
Avalle, L.; Raggi, L.; Monteleone, E.; Savino, A.; Viavattene, D.; Statello, L.; Camperi, A.; Stabile, S.A.; Salemme, V.; De Marzo, N.; Marino, F.; Guglielmi, C.; Lobascio, A.; Zanini, C.; Forni, M.; Incarnato, D.; Defilippi, P.; Oliviero, S.; Poli, V. STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts. Oncogene, 2022, 41(10), 1456-1467.
[http://dx.doi.org/10.1038/s41388-021-02172-y] [PMID: 35042959]
[36]
Liu, H.; Mei, Y.; Ma, X.; Zhang, X.; Nie, W. FRZB is regulated by the transcription factor EGR1 and inhibits the growth and invasion of triple-negative breast cancer cells by regulating the JAK/STAT3 pathway. Clin. Breast Cancer, 2022, 22(7), 690-698.
[http://dx.doi.org/10.1016/j.clbc.2022.05.010] [PMID: 35787980]
[37]
Kortylewski, M.; Kujawski, M.; Wang, T.; Wei, S.; Zhang, S.; Pilon-Thomas, S.; Niu, G.; Kay, H.; Mulé, J.; Kerr, W.G.; Jove, R.; Pardoll, D.; Yu, H. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med., 2005, 11(12), 1314-1321.
[http://dx.doi.org/10.1038/nm1325] [PMID: 16288283]
[38]
Du, Y.; Tu, G.; Yang, G.; Li, G.; Yang, D.; Lang, L.; Xi, L.; Sun, K.; Chen, Y.; Shu, K.; Liao, H.; Liu, M.; Hou, Y. MiR-205/YAP1 in activated fibroblasts of breast tumor promotes vegf-independent angiogenesis through STAT3 signaling. Theranostics, 2017, 7(16), 3972-3988.
[http://dx.doi.org/10.7150/thno.18990] [PMID: 29109792]
[39]
Roskoski, R. Jr Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol. Res., 2016, 111, 784-803.
[http://dx.doi.org/10.1016/j.phrs.2016.07.038] [PMID: 27473820]
[40]
Liu, Z.; Wang, H.; Guan, L.; Lai, C.; Yu, W.; Lai, M. LL1, a novel and highly selective STAT3 inhibitor, displays anti‐colorectal cancer activities in vitro and in vivo. Br. J. Pharmacol., 2020, 177(2), 298-313.
[http://dx.doi.org/10.1111/bph.14863] [PMID: 31499589]

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