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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

Alkylamino Phenol Derivative Induces Apoptosis by Inhibiting EGFR Signaling Pathway in Breast Cancer Cells

Author(s): Suresh Palanivel, Olli Yli-Harja and Meenakshisundaram Kandhavelu*

Volume 20, Issue 7, 2020

Page: [809 - 819] Pages: 11

DOI: 10.2174/1871520620666200213101407

Price: $65

Abstract

Background and Objective: The present study was carried out to evaluate the anticancer property of an alkylamino phenol derivative -2-((3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol) (THTMP) against human breast cancer cells. The cytotoxicity of the THTMP was assessed to know its specificity towards breast cancer cells without affecting the normal cells.

Methods: The THTMP was synthesized and the cytotoxicity was assessed by MTT assay, Caspases enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR and QSAR. In addition, ADME analysis was executed to understand the mode of action of THTMP.

Results: THTMP showed potential cytotoxic activity against the growth of MCF7 and SK-BR3 cells with the IC50 values of 87.92μM and 172.51μM, respectively. Interestingly, THTMP found to activate caspase 3 and caspase 9 enzymes in cancer cells, which are the key enzymes implicated in apoptosis. THTMP induced apoptosis in which 33% of the cells entered the late apoptotic stage after 24h of treatment. The results also revealed that the apoptotic response could be influenced by the association of THTMP with the Epidermal Growth Factor Receptor (EGFR) mediated inhibition of the Phosphatidylinositol 3-Kinase (PI3K)/S6K1 signaling pathway. In addition, docking was performed to study the binding mode of the THTMP, which shows better interaction with EGFR. The structural elucidation of THTMP by Quantitative Structure-Activity Relationship model (QSAR) and ADMET screening suggested, THTMP as an effective anticancer compound.

Conclusion: This work strengthens the potential of a promising drug-like compound, THTMP, for the discovery of anticancer drug against breast cancer.

Keywords: Phenol derivative, breast cancer cells, apoptosis, PI3K/AKT pathway, ADME, EGFR.

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[1]
Bray, F.; Ren, J-S.; Masuyer, E.; Ferlay, J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int. J. Cancer, 2013, 132(5), 1133-1145.
[http://dx.doi.org/10.1002/ijc.27711] [PMID: 22752881]
[2]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin., 2013, 63(1), 11-30.
[http://dx.doi.org/10.3322/caac.21166] [PMID: 23335087]
[3]
Breast cancer in developing countries. Lancet, 2009, 374(9701), 1567.
[http://dx.doi.org/10.1016/S0140-6736(09)61930-9] [PMID: 19897110]
[4]
Liu, J.; Ming, B.; Gong, G-H.; Wang, D.; Bao, G-L.; Yu, L-J. Current research on anti-breast cancer synthetic compounds. RSC Advances, 2018, 8, 4386-4416.
[http://dx.doi.org/10.1039/C7RA12912B]
[5]
Mullard, A. 2017 FDA drug approvals. Nat. Rev. Drug Discov., 2018, 17(2), 150.
[http://dx.doi.org/10.1038/nrd.2018.18] [PMID: 29386602]
[6]
Gerl, R.; Vaux, D.L. Apoptosis in the development and treatment of cancer. Carcinogenesis, 2005, 26(2), 263-270.
[http://dx.doi.org/10.1093/carcin/bgh283] [PMID: 15375012]
[7]
Wong, R.S.Y. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30(1), 87.
[http://dx.doi.org/10.1186/1756-9966-30-87] [PMID: 21943236]
[8]
Kwan, Y.P. Evaluation of the cytotoxicity, cell-cycle arrest, and apoptotic induction by Euphorbia hirta in MCF-7 breast cancer cells. Pharm. Biol., 2015, 54(7), 1-14.
[http://dx.doi.org/10.3109/13880209.2015.1064451] [PMID: 26154521]
[9]
Zhang, N.; Kong, X.; Yan, S.; Yuan, C.; Yang, Q. Huaier aqueous extract inhibits proliferation of breast cancer cells by inducing apoptosis. Cancer Sci., 2010, 101(11), 2375-2383.
[http://dx.doi.org/10.1111/j.1349-7006.2010.01680.x] [PMID: 20718753]
[10]
Tor, Y.S.; Yazan, L.S.; Foo, J.B.; Wibowo, A.; Ismail, N.; Cheah, Y.K.; Abdullah, R.; Ismail, M.; Ismail, I.S.; Yeap, S.K. Induction of apoptosis in MCF-7 cells via Oxidative Stress Generation, mitochondria-dependent and caspase-independent pathway by ethyl acetate extract of Dillenia suffruticosa and its chemical profile. PLoS One, 2015, 10(6), e0127441
[http://dx.doi.org/10.1371/journal.pone.0127441] [PMID: 26047480]
[11]
Mariño, G.; Niso-Santano, M.; Baehrecke, E.H.; Kroemer, G. Self-consumption: the interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol., 2014, 15(2), 81-94.
[http://dx.doi.org/10.1038/nrm3735] [PMID: 24401948]
[12]
Cotelle, N.; Bernier, J.L.; Catteau, J.P.; Pommery, J.; Wallet, J.C.; Gaydou, E.M. Antioxidant properties of hydroxy-flavones. Free Radic. Biol. Med., 1996, 20(1), 35-43.
[http://dx.doi.org/10.1016/0891-5849(95)02014-4] [PMID: 8903677]
[13]
Larson, R.A. The antioxidants of higher plants. Phytochemistry, 1988, 27(4), 969-978.
[http://dx.doi.org/10.1016/0031-9422(88)80254-1]
[14]
Velioglu, Y.S.; Mazza, G.; Gao, L.; Oomah, B.D. Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J. Agric. Food Chem., 1998, 46(10), 4113-4117.
[http://dx.doi.org/10.1021/jf9801973]
[15]
Zheng, W.; Wang, S.Y. Antioxidant activity and phenolic compounds in selected herbs. J. Agric. Food Chem., 2001, 49(11), 5165-5170.
[http://dx.doi.org/10.1021/jf010697n] [PMID: 11714298]
[16]
Jaganathan, S.K.; Supriyanto, E. Antiproliferative and molecular mechanism of eugenol-induced apoptosis in cancer cells. Molecules, 2012, 17(6), 6290-6304.
[http://dx.doi.org/10.3390/molecules17066290] [PMID: 22634840]
[17]
Doan, P.; Karjalainen, A.; Chandraseelan, J.G.; Sandberg, O.; Yli-Harja, O.; Rosholm, T.; Franzen, R.; Candeias, N.R.; Kandhavelu, M. Synthesis and biological screening for cytotoxic activity of N-substituted indolines and morpholines. Eur. J. Med. Chem., 2016, 120, 296-303.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.024] [PMID: 27214140]
[18]
Klijn, J.G.; Berns, P.M.; Schmitz, P.I.; Foekens, J.A. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr. Rev., 1992, 13(1), 3-17.
[PMID: 1313356]
[19]
Ciruelos Gil, E.M. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat. Rev., 2014, 40(7), 862-871.
[http://dx.doi.org/10.1016/j.ctrv.2014.03.004] [PMID: 24774538]
[20]
She, Q-B.; Gruvberger-Saal, S.K.; Maurer, M.; Chen, Y.; Jumppanen, M.; Su, T.; Dendy, M.; Lau, Y.K.; Memeo, L.; Horlings, H.M.; van de Vijver, M.J.; Isola, J.; Hibshoosh, H.; Rosen, N.; Parsons, R.; Saal, L.H. Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer, 2016, 16(1), 587.
[http://dx.doi.org/10.1186/s12885-016-2609-2] [PMID: 27484095]
[21]
Subik, K. The expression patterns of ER, PR, HER2, CK5/6, EGFR, KI-67 and AR by immunohistochemical analysis in breast cancer cell lines Breast Cancer Basic. Clin. Res., 2010, 4
[http://dx.doi.org/10.1177/117822341000400004]
[22]
Peng, K.; Tian, X.; Qian, Y.; Skibba, M.; Zou, C.; Liu, Z.; Wang, J.; Xu, Z.; Li, X.; Liang, G. Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II. J. Cell. Mol. Med., 2016, 20(3), 482-494.
[http://dx.doi.org/10.1111/jcmm.12763] [PMID: 26762600]
[23]
Vaiyapuri, P.S.; Ali, A.A.; Mohammad, A.A.; Kandhavelu, J.; Kandhavelu, M. Time lapse microscopy observation of cellular structural changes and image analysis of drug treated cancer cells to characterize the cellular heterogeneity. Environ. Toxicol., 2015, 30(6), 724-734.
[http://dx.doi.org/10.1002/tox.21950] [PMID: 24446218]
[24]
Neto, Í.; Andrade, J.; Fernandes, A.S.; Pinto Reis, C.; Salunke, J.K.; Priimagi, A.; Candeias, N.R.; Rijo, P. Multicomponent petasis-borono mannich preparation of alkylaminophenols and antimicrobial activity studies. ChemMedChem, 2016, 11(18), 2015-2023.
[http://dx.doi.org/10.1002/cmdc.201600244] [PMID: 27457409]
[25]
Doan, P.; Musa, A.; Candeias, N.R.; Emmert-Streib, F.; Yli-Harja, O.; Kandhavelu, M. Alkylaminophenol induces G1/S phase cell cycle arrest in glioblastoma cells through p53 and cyclin-dependent kinase signaling pathway. Front. Pharmacol., 2019, 10, 330.
[http://dx.doi.org/10.3389/fphar.2019.00330] [PMID: 31001122]
[26]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[27]
Herrmann, M.; Lorenz, H.M.; Voll, R.; Grünke, M.; Woith, W.; Kalden, J.R. A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Res., 1994, 22(24), 5506-5507.
[http://dx.doi.org/10.1093/nar/22.24.5506] [PMID: 7816645]
[28]
Soror, A.S.; Alla, A.S.; El-Ayouty, Y.M.; Gehan, H.A. Cytotoxicity, DNA fragmentation and histological analysis of MCF-7 cells treated with acetylspermine. Int. J. Pharmacol., 2015, 11(7), 712-718.
[http://dx.doi.org/10.3923/ijp.2015.712.718]
[29]
Basnakian, A.G.; James, S.J. A rapid and sensitive assay for the detection of DNA fragmentation during early phases of apoptosis. Nucleic Acids Res., 1994, 22(13), 2714-2715.
[http://dx.doi.org/10.1093/nar/22.13.2714] [PMID: 8041637]
[30]
Vermes, I.; Haanen, C.; Steffens-Nakken, H.; Reutelingsperger, C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J. Immunol. Methods, 1995, 184(1), 39-51.
[http://dx.doi.org/10.1016/0022-1759(95)00072-I] [PMID: 7622868]
[31]
Koopman, G.; Reutelingsperger, C.P.; Kuijten, G.A.; Keehnen, R.M.; Pals, S.T.; van Oers, M.H. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood, 1994, 84(5), 1415-1420.
[http://dx.doi.org/10.1182/blood.V84.5.1415.bloodjournal8451415] [PMID: 8068938]
[32]
Chomczynski, P.; Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem., 1987, 162(1), 156-159.
[http://dx.doi.org/10.1016/0003-2697(87)90021-2] [PMID: 2440339]
[33]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible. J. Mol. Biol., 1997, 267(3), 727-748.
[http://dx.doi.org/10.1006/jmbi.1996.0897]
[34]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[http://dx.doi.org/10.1021/ci300367a] [PMID: 23092397]
[35]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[http://dx.doi.org/10.1093/nar/gkv951] [PMID: 26400175]
[36]
Cridge, B.J.; Larsen, L.; Rosengren, R.J. Curcumin and its derivatives in breast cancer: Current developments and potential for the treatment of drug-resistant cancers. Oncol. Discov., 2013, 1(1), 6.
[http://dx.doi.org/10.7243/2052-6199-1-6]
[37]
Doan, P.; Nguyen, T.; Yli-Harja, O.; Candeias, N.R.; Kandhavelu, M. Effect of alkylaminophenols on growth inhibition and apoptosis of bone cancer cells. Eur. J. Pharm. Sci., 2017, 107, 208-216.
[http://dx.doi.org/10.1016/j.ejps.2017.07.016] [PMID: 28728976]
[38]
Sukhramani, P.S.; Sukhramani, P.S.; Desai, S.A.; Suthar, M.P. In vitro cytotoxicity evaluation of novel N-substituted bis-benzimidazole derivatives for anti-lung and anti-breast cancer activity. Ann. Biol. Res., 2011, 2(1), 51-59.
[39]
Ghorab, M.M.; Alsaid, M.S. Anticancer activity of some novel thieno [2, 3-d] pyrimidine derivatives. Biomed. Res., 2016, 27(1), 110-115.
[40]
Malek, S.N.A. Cytotoxic activity of Pereskia bleo (Cactaceae) against selected human cell lines. Int. J. Cancer Res., 2008, 4(1), 20-27.
[http://dx.doi.org/10.3923/ijcr.2008.20.27]
[41]
Vairavelu, L. Synthesis, biological evaluation and structure activity relationship of substituted pyrazolo-, isoxazolo-, pyrimido- and mercaptopyrimidocycloocta[b]indoles. Med. Chem. (Los Angeles), 2016, 6(05), 20-27.
[42]
Gaur, R.; Pathania, A.S.; Malik, F.A.; Bhakuni, R.S.; Verma, R.K. Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity. Eur. J. Med. Chem., 2016, 122, 232-246.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.035] [PMID: 27371926]
[43]
Feng, C.; Zhou, L.Y.; Yu, T.; Xu, G.; Tian, H.L.; Xu, J.J.; Xu, H.X.; Luo, K.Q. A new anticancer compound, oblongifolin C, inhibits tumor growth and promotes apoptosis in HeLa cells through Bax activation. Int. J. Cancer, 2012, 131(6), 1445-1454.
[http://dx.doi.org/10.1002/ijc.27365] [PMID: 22116711]
[44]
Sawadogo, W.R.; Le Douaron, G.; Maciuk, A.; Bories, C.; Loiseau, P.M.; Figadère, B.; Guissou, I.P.; Nacoulma, O.G. In vitro antileishmanial and antitrypanosomal activities of five medicinal plants from Burkina Faso. Parasitol. Res., 2012, 110(5), 1779-1783.
[http://dx.doi.org/10.1007/s00436-011-2699-3] [PMID: 22037827]
[45]
Walsh, J.G.; Cullen, S.P.; Sheridan, C.; Lüthi, A.U.; Gerner, C.; Martin, S.J. Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 12815-12819.
[http://dx.doi.org/10.1073/pnas.0707715105] [PMID: 18723680]
[46]
Eastman, A.; Barry, M.A. The origins of DNA breaks: a consequence of DNA damage, DNA repair, or apoptosis? Cancer Invest., 1992, 10(3), 229-240.
[http://dx.doi.org/10.3109/07357909209032765] [PMID: 1316202]
[47]
Baskić, D.; Popović, S.; Ristić, P.; Arsenijević, N.N. Analysis of cycloheximide-induced apoptosis in human leukocytes: fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol. Int., 2006, 30(11), 924-932.
[http://dx.doi.org/10.1016/j.cellbi.2006.06.016] [PMID: 16895761]
[48]
Laskowski, R.A. PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res., 2001, 29(1), 221-222.
[http://dx.doi.org/10.1093/nar/29.1.221] [PMID: 11125097]
[49]
Anantharaju, P.G.; Gowda, P.C.; Vimalambike, M.G.; Madhunapantula, S.V. An overview on the role of dietary phenolics for the treatment of cancers. Nutr. J., 2016, 15(1), 99.
[http://dx.doi.org/10.1186/s12937-016-0217-2] [PMID: 27903278]
[50]
Aggarwal, B.B.; Kumar, A.; Bharti, A.C. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res., 2003, 23(1A), 363-398.
[PMID: 12680238]
[51]
Kampa, M.; Alexaki, V.I.; Notas, G.; Nifli, A.P.; Nistikaki, A.; Hatzoglou, A.; Bakogeorgou, E.; Kouimtzoglou, E.; Blekas, G.; Boskou, D.; Gravanis, A.; Castanas, E. Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: potential mechanisms of action. Breast Cancer Res., 2004, 6(2), R63-R74.
[http://dx.doi.org/10.1186/bcr752] [PMID: 14979919]
[52]
Chen, C-J.; Mei Hua,, H.;; Kuo, S.C.; Lai, Y.Y.; Chung, J.G.; Liu,, W. (2E)-N,N-dibutyl-3-(4-hydroxy-3-methoxyphenyl)acrylamide induces apoptosis and cell cycle arrest in HL-60 cells. Anticancer Res., 2007, 27, 343-349.
[53]
Beltz, L.A.; Bayer, D.K.; Moss, A.L.; Simet, I.M. Mechanisms of cancer prevention by green and black tea polyphenols. Anticancer. Agents Med. Chem., 2006, 6(5), 389-406.
[http://dx.doi.org/10.2174/187152006778226468] [PMID: 17017850]

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