Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Implications and Efficacy of Aromatase Inhibitors in Combination and Monotherapy for the Treatment of Lung Cancer

Author(s): Bayan A. Rahal and Sanaa K. Bardaweel*

Volume 22, Issue 18, 2022

Published on: 15 July, 2022

Page: [3114 - 3124] Pages: 11

DOI: 10.2174/1871520622666220426112435

Price: $65

Abstract

Background: Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation.

Methods: The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells’ capability to form colonies.

Result: Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC50 values after 48 hours of treatment with exemestane were 176, 180, and 120 μM in A549, H661, and H1299, respectively. Curcumin IC50 values after 48 hours were 80, 43, and 68 μM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 μM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 μM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells.

Conclusion: Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.

Keywords: Aromatase inhibitors, lung cancer, curcumin, exemestane, apoptosis, synergism.

« Previous Next »
Graphical Abstract

[1]
Bade, B.C.; Dela Cruz, C.S. Lung cancer 2020: Epidemiology, etiology, and prevention. Clin. Chest Med., 2020, 41(1), 1-24.
[http://dx.doi.org/10.1016/j.ccm.2019.10.001] [PMID: 32008623]
[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of inci-dence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Miki, Y.; Abe, K.; Suzuki, S.; Suzuki, T.; Sasano, H. Suppression of estrogen actions in human lung cancer. Mol. Cell. Endocrinol., 2011, 340(2), 168-174.
[http://dx.doi.org/10.1016/j.mce.2011.02.018] [PMID: 21354461]
[4]
Verma, M.K.; Miki, Y.; Sasano, H. Aromatase in human lung carcinoma. Steroids, 2011, 76(8), 759-764.
[http://dx.doi.org/10.1016/j.steroids.2011.02.020] [PMID: 21392519]
[5]
Burns, T.F.; Stabile, L.P. Targeting the estrogen pathway for the treatment and prevention of lung cancer. Lung Cancer Manag., 2014, 3(1), 43-52.
[http://dx.doi.org/10.2217/lmt.13.67] [PMID: 25395992]
[6]
Miller, W.R.; Bartlett, J.; Brodie, A.M.; Brueggemeier, R.W.; di Salle, E.; Lønning, P.E.; Llombart, A.; Maass, N.; Maudelonde, T.; Sasano, H.; Goss, P.E. Aromatase inhibitors: Are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist, 2008, 13(8), 829-837.
[http://dx.doi.org/10.1634/theoncologist.2008-0055] [PMID: 18695261]
[7]
Ashrafizadeh, M.; Najafi, M.; Makvandi, P.; Zarrabi, A.; Farkhondeh, T.; Samarghandian, S. Versatile role of curcumin and its derivatives in lung cancer therapy. J. Cell. Physiol., 2020, 235(12), 9241-9268.
[http://dx.doi.org/10.1002/jcp.29819] [PMID: 32519340]
[8]
Rodríguez Castaño, P.; Parween, S.; Pandey, A.V. Bioactivity of curcumin on the cytochrome P450 enzymes of the steroidogenic pathway. Int. J. Mol. Sci., 2019, 20(18), 4606.
[http://dx.doi.org/10.3390/ijms20184606] [PMID: 31533365]
[9]
Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; Norris, A.; Sanseau, P.; Cavalla, D.; Pirmohamed, M. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov., 2019, 18(1), 41-58.
[http://dx.doi.org/10.1038/nrd.2018.168] [PMID: 30310233]
[10]
Bardaweel, S.K.; Tawaha, K.A.; Hudaib, M.M. Antioxidant, antimicrobial and antiproliferative activities of Anthemis palestina essential oil. BMC Complement. Altern. Med., 2014, 14(1), 297.
[http://dx.doi.org/10.1186/1472-6882-14-297] [PMID: 25112895]
[11]
Rodriguez, L.G.; Wu, X.; Guan, J.L. Wound-healing assay. Cell migration; Humana Press, 2005, pp. 23-29.
[12]
Rodriguez-Lara, V.; Hernandez-Martinez, J.M.; Arrieta, O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J. Thorac. Dis., 2018, 10(1), 482-497.
[http://dx.doi.org/10.21037/jtd.2017.12.61] [PMID: 29600083]
[13]
Ikeda, K.; Horie-Inoue, K.; Inoue, S. Identification of estrogen-responsive genes based on the DNA binding properties of estrogen recep-tors using high-throughput sequencing technology. Acta Pharmacol. Sin., 2015, 36(1), 24-31.
[http://dx.doi.org/10.1038/aps.2014.123] [PMID: 25500870]
[14]
Chumsri, S.; Howes, T.; Bao, T.; Sabnis, G.; Brodie, A. Aromatase, aromatase inhibitors, and breast cancer. J. Steroid Biochem. Mol. Biol., 2011, 125(1-2), 13-22.
[http://dx.doi.org/10.1016/j.jsbmb.2011.02.001] [PMID: 21335088]
[15]
Koutras, A.; Giannopoulou, E.; Kritikou, I.; Antonacopoulou, A.; Evans, T.R.; Papavassiliou, A.G.; Kalofonos, H. Antiproliferative effect of exemestane in lung cancer cells. Mol. Cancer, 2009, 8(1), 109.
[http://dx.doi.org/10.1186/1476-4598-8-109] [PMID: 19930708]
[16]
Liu, F.; Gao, S.; Yang, Y.; Zhao, X.; Fan, Y.; Ma, W.; Yang, D.; Yang, A.; Yu, Y. Curcumin induced autophagy anticancer effects on hu-man lung adenocarcinoma cell line A549. Oncol. Lett., 2017, 14(3), 2775-2782.
[http://dx.doi.org/10.3892/ol.2017.6565] [PMID: 28928819]
[17]
Wang, Y.; Lu, J.; Jiang, B.; Guo, J. The roles of curcumin in regulating the tumor immunosuppressive microenvironment. Oncol. Lett., 2020, 19(4), 3059-3070.
[http://dx.doi.org/10.3892/ol.2020.11437] [PMID: 32256807]
[18]
Shen, D.W.; Pouliot, L.M.; Hall, M.D.; Gottesman, M.M. Cisplatin resistance: A cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol. Rev., 2012, 64(3), 706-721.
[http://dx.doi.org/10.1124/pr.111.005637] [PMID: 22659329]
[19]
Tkalia, I.G.; Vorobyova, L.I.; Grabovoy, A.N.; Svintsitsky, V.S.; Tarasova, T.O. The antitumor efficacy of cisplatin in combination with triptorelin and exemestane therapy for an ovarian cancer ascites model in Wistar rats. Exp. Oncol., 2015, 37(1), 30-35.
[http://dx.doi.org/10.31768/2312-8852.2015.37(1):30-35] [PMID: 25804228]
[20]
Chen, S.; Gao, W.; Zhang, M.J.; Chan, J.Y.W.; Wong, T.S. Curcumin enhances cisplatin sensitivity by suppressing NADPH oxidase 5 expression in human epithelial cancer. Oncol. Lett., 2019, 18(2), 2132-2139.
[http://dx.doi.org/10.3892/ol.2019.10479] [PMID: 31423287]
[21]
Duarte, V.M.; Han, E.; Veena, M.S.; Salvado, A.; Suh, J.D.; Liang, L.J.; Faull, K.F.; Srivatsan, E.S.; Wang, M.B. Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway. Mol. Cancer Ther., 2010, 9(10), 2665-2675.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0064] [PMID: 20937593]
[22]
Gökçe Kütük, S.; Gökçe, G.; Kütük, M.; Gürses Cila, H.E.; Nazıroğlu, M. Curcumin enhances cisplatin-induced human laryngeal squa-mous cancer cell death through activation of TRPM2 channel and mitochondrial oxidative stress. Sci. Rep., 2019, 9(1), 17784.
[http://dx.doi.org/10.1038/s41598-019-54284-x] [PMID: 31780732]
[23]
Mirkin, S.; Pickar, J.H. Selective estrogen receptor modulators (SERMs): A review of clinical data. Maturitas, 2015, 80(1), 52-57.
[http://dx.doi.org/10.1016/j.maturitas.2014.10.010] [PMID: 25466304]
[24]
Alsous, L.; Bardaweel, S. Selective Estrogen Receptor Modulators (SERMs) Synergize with Cisplatin, induce apoptosis and Suppress Cel-lular Migration and Colony Formation of Lung Cancer Cells. Anticancer. Agents Med. Chem., 2021, 21, 1-1.
[http://dx.doi.org/10.2174/1871520621666210908110902]
[25]
Traina, T.A.; Poggesi, I.; Robson, M.; Asnis, A.; Duncan, B.A.; Heerdt, A.; Dang, C.; Lake, D.; Moasser, M.; Panageas, K.; Borgen, P.; Norton, L.; Hudis, C.; Dickler, M.N. Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer. Breast Cancer Res. Treat., 2008, 111(2), 377-388.
[http://dx.doi.org/10.1007/s10549-007-9787-1] [PMID: 17952589]
[26]
Abou-Issa, H.; Alshafie, G. Celecoxib: A novel treatment for lung cancer. Expert Rev. Anticancer Ther., 2004, 4(5), 725-734.
[http://dx.doi.org/10.1586/14737140.4.5.725] [PMID: 15485309]
[27]
Falandry, C.; Debled, M.; Bachelot, T.; Delozier, T.; Crétin, J.; Romestaing, P.; Mille, D.; You, B.; Mauriac, L.; Pujade-Lauraine, E.; Freyer, G. Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: A double-blind phase III GINECO study. Breast Cancer Res. Treat., 2009, 116(3), 501-508.
[http://dx.doi.org/10.1007/s10549-008-0229-5] [PMID: 19020973]
[28]
Giannopoulou, E.; Siatis, K.E.; Metsiou, D.; Kritikou, I.; Papachristou, D.J.; Kalofonou, M.; Koutras, A.; Athanassiou, G.; Kalofonos, H.P. The inhibition of aromatase alters the mechanical and rheological properties of non-small-cell lung cancer cell lines affecting cell mi-gration. Biochim. Biophys. Acta, 2015, 1853(2), 328-337.
[http://dx.doi.org/10.1016/j.bbamcr.2014.11.016] [PMID: 25450981]
[29]
Borowicz, S.; Van Scoyk, M.; Avasarala, S.; Karuppusamy Rathinam, M.K.; Tauler, J.; Bikkavilli, R.K.; Winn, R.A. The soft agar colony formation assay. J. Vis. Exp., 2014, (92), e51998-e51998.
[PMID: 25408172]
[30]
Guo, Y.; Shu, L.; Zhang, C.; Su, Z.Y.; Kong, A.N.T. Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochem. Pharmacol., 2015, 94(2), 69-78.
[http://dx.doi.org/10.1016/j.bcp.2015.01.009] [PMID: 25640947]
[31]
Boersma, H.H.; Kietselaer, B.L.; Stolk, L.M.; Bennaghmouch, A.; Hofstra, L.; Narula, J.; Heidendal, G.A.K.; Reutelingsperger, C.P. Past, present, and future of annexin A5: From protein discovery to clinical applications. J. Nucl. Med., 2005, 46(12), 2035-2050.
[PMID: 16330568]
[32]
Vermes, I.; Haanen, C.; Steffens-Nakken, H.; Reutelingsperger, C. A novel assay for apoptosis. Flow cytometric detection of phosphati-dylserine 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]
[33]
Amaral, C.; Borges, M.; Melo, S.; da Silva, E.T.; Correia-da-Silva, G.; Teixeira, N. Apoptosis and autophagy in breast cancer cells follow-ing exemestane treatment. PLoS One, 2012, 7(8), e42398-e42398.
[http://dx.doi.org/10.1371/journal.pone.0042398] [PMID: 22912703]

Rights & Permissions Print Cite
Article Metrics
17
© 2024 Bentham Science Publishers | Privacy Policy