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

Molecular and Metabolomic Investigation of Celecoxib Antiproliferative Activity in Mono-and Combination Therapy against Breast Cancer Cell Models

Author(s): Sanaa K. Bardaweel*, Lina A. Dahabiyeh, Bushra M. Akileh, Dana D. Shalabi, Afnan K. AlHiary, Judy Pawling, James W. Dennis and Anas M. Abdel Rahman

Volume 22, Issue 8, 2022

Published on: 10 September, 2021

Page: [1611 - 1621] Pages: 11

DOI: 10.2174/1871520621666210910101349

Price: $65

Abstract

Background: Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer.

Objectives: This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity.

Methods: The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment.

Results: Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells.

Conclusion: Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition.

Keywords: Breast cancer, NSAIDs, celecoxib, metabolomics, combination therapy, raloxifene.

« Previous Next »
Graphical Abstract

[1]
Ghoncheh, M.; Pournamdar, Z.; Salehiniya, H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac. J. Cancer Prev., 2016, 17(S3), 43-46.
[http://dx.doi.org/10.7314/APJCP.2016.17.S3.43] [PMID: 27165206]
[2]
Waks, A.G.; Winer, E.P. Breast cancer treatment: A review. JAMA, 2019, 321(3), 288-300.
[http://dx.doi.org/10.1001/jama.2018.19323] [PMID: 30667505]
[3]
American Cancer Society. How common is breast cancer?, 2020. Available from: https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html
[4]
Redig, A.J.; McAllister, S.S. Breast cancer as a systemic disease: A view of metastasis. J. Intern. Med., 2013, 274(2), 113-126.
[http://dx.doi.org/10.1111/joim.12084] [PMID: 23844915]
[5]
Landskron, G.; De la Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res., 2014.149185
[6]
Soslow, R.A.; Dannenberg, A.J.; Rush, D.; Woerner, B.M.; Khan, K.N.; Masferrer, J.; Koki, A.T. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer, 2000, 89(12), 2637-2645.
[http://dx.doi.org/10.1002/1097-0142(20001215)89:12<2637:AID-CNCR17>3.0.CO;2-B] [PMID: 11135226]
[7]
Cashman, J.N. The mechanisms of action of NSAIDs in analgesia. Drugs, 1996, 52(Suppl. 5), 13-23.
[http://dx.doi.org/10.2165/00003495-199600525-00004] [PMID: 8922554]
[8]
Hida, T.; Yatabe, Y.; Achiwa, H.; Muramatsu, H.; Kozaki, K.; Nakamura, S.; Ogawa, M.; Mitsudomi, T.; Sugiura, T.; Takahashi, T. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res., 1998, 58(17), 3761-3764.
[PMID: 9731479]
[9]
Maier, T.J.; Schilling, K.; Schmidt, R.; Geisslinger, G.; Grösch, S. Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem. Pharmacol., 2004, 67(8), 1469-1478.
[http://dx.doi.org/10.1016/j.bcp.2003.12.014] [PMID: 15041464]
[10]
Gallo, O.; Masini, E.; Bianchi, B.; Bruschini, L.; Paglierani, M.; Franchi, A. Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma. Hum. Pathol., 2002, 33(7), 708-714.
[http://dx.doi.org/10.1053/hupa.2002.125376] [PMID: 12196922]
[11]
Bhardwaj, A.; Kaur, J.; Wuest, F.; Knaus, E.E. Fluorophore-labeled cyclooxygenase-2 inhibitors for the imaging of cyclooxygenase-2 overexpression in cancer: Synthesis and biological studies. ChemMedChem, 2014, 9(1), 109-116, 240.
[http://dx.doi.org/10.1002/cmdc.201300355] [PMID: 24376205]
[12]
Kang, H.F.; Wang, X.J.; Liu, X.X.; Dai, Z.J.; Xue, F.J.; Xue, X.H. Chemopreventive effect of celecoxib against DMBA-induced breast cancer and its mechanism. Nan Fang Yi Ke Da Xue Xue Bao, 2006, 26(11), 1599-1602.
[PMID: 17121709]
[13]
Elder, D.J.; Halton, D.E.; Hague, A.; Paraskeva, C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: Independence from COX-2 protein expression. Clin. Cancer Res., 1997, 3(10), 1679-1683.
[PMID: 9815550]
[14]
Chan, T.A.; Morin, P.J.; Vogelstein, B.; Kinzler, K.W. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc. Natl. Acad. Sci. USA, 1998, 95(2), 681-686.
[http://dx.doi.org/10.1073/pnas.95.2.681] [PMID: 9435252]
[15]
Hanif, R.; Pittas, A.; Feng, Y.; Koutsos, M.I.; Qiao, L.; Staiano-Coico, L.; Shiff, S.I.; Rigas, B. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem. Pharmacol., 1996, 52(2), 237-245.
[http://dx.doi.org/10.1016/0006-2952(96)00181-5] [PMID: 8694848]
[16]
Brideau, C.; Kargman, S.; Liu, S.; Dallob, A.L.; Ehrich, E.W.; Rodger, I.W.; Chan, C.C. A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. Inflamm. Res., 1996, 45(2), 68-74.
[http://dx.doi.org/10.1007/BF02265118] [PMID: 8907587]
[17]
Tfayli, A.; Yang, J.; Kojouri, K.; Kesserwan, C.; Jafari, M.; Ozer, H. Neoadjuvant therapy with celecoxib to women with early stage breast cancer. Neoplasma, 2008, 55(2), 122-126.
[PMID: 18237249]
[18]
Aristarco, V.; Serrano, D.; Gandini, S.; Johansson, H.; Macis, D.; Guerrieri-Gonzaga, A.; Lazzeroni, M.; Feroce, I.; Pruneri, G.; Pagani, G.; Toesca, A.; Caldarella, P.; DeCensi, A.; Bonanni, B. A randomized, placebo-controlled, phase II, presurgical biomarker trial of celecoxib versus exemestane in postmenopausal breast cancer patients. Cancer Prev. Res. (Phila.), 2016, 9(5), 349-356.
[http://dx.doi.org/10.1158/1940-6207.CAPR-15-0311] [PMID: 26928670]
[19]
Lustberg, M.B.; Povoski, S.P.; Zhao, W.; Ziegler, R.M.; Sugimoto, Y.; Ruppert, A.S.; Lehman, A.M.; Shiels, D.R.; Mrozek, E.; Ramaswamy, B.; Layman, R.M.; Brueggemeier, R.W.; Shapiro, C.L. Phase II trial of neoadjuvant exemestane in combination with celecoxib in postmenopausal women who have breast cancer. Clin. Breast Cancer, 2011, 11(4), 221-227.
[http://dx.doi.org/10.1016/j.clbc.2011.03.022] [PMID: 21729671]
[20]
Falandry, C.; Canney, P.A.; Freyer, G.; Dirix, L.Y. Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer. Ann. Oncol., 2009, 20(4), 615-620.
[http://dx.doi.org/10.1093/annonc/mdn693] [PMID: 19254941]
[21]
Abdel Rahman, A.M.; Pawling, J.; Ryczko, M.; Caudy, A.A.; Dennis, J.W. Targeted metabolomics in cultured cells and tissues by mass spectrometry: Method development and validation. Anal. Chim. Acta, 2014, 845(845), 53-61.
[http://dx.doi.org/10.1016/j.aca.2014.06.012] [PMID: 25201272]
[22]
Gennari, L.; Merlotti, D.; Paola, V.D.; Nuti, R. Raloxifene in breast cancer prevention. Expert Opin. Drug Saf., 2008, 7(3), 259-270.
[http://dx.doi.org/10.1517/14740338.7.3.259] [PMID: 18462184]
[23]
Chong, J.; Soufan, O.; Li, C.; Caraus, I.; Li, S.; Bourque, G.; Wishart, D.S.; Xia, J. MetaboAnalyst 4.0: Towards more transparent and integrative metabolomics analysis. Nucleic Acids Res., 2018, 46(W1), W486-W494.
[http://dx.doi.org/10.1093/nar/gky310] [PMID: 29762782]
[24]
Worley, B.; Powers, R. Multivariate analysis in metabolomics. Curr. Metabolomics, 2013, 1(1), 92-107.
[PMID: 26078916]
[25]
Yin, P.; Wan, D.; Zhao, C.; Chen, J.; Zhao, X.; Wang, W.; Lu, X.; Yang, S.; Gu, J.; Xu, G. A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry. Mol. Biosyst., 2009, 5(8), 868-876.
[http://dx.doi.org/10.1039/b820224a] [PMID: 19603122]
[26]
Ihraiz, W.G.; Ahram, M.; Bardaweel, S.K. Proton pump inhibitors enhance chemosensitivity, promote apoptosis, and suppress migration of breast cancer cells. Acta Pharm., 2020, 70(2), 179-190.
[http://dx.doi.org/10.2478/acph-2020-0020] [PMID: 31955147]
[27]
Bardaweel, S.K.; Alsalamat, H.A.; Aleidi, S.M.; Bashatwah, R.M. Glucose deprivation enhances the antiproliferative effects of oral hypoglycemic biguanides in different molecular subtypes of breast cancer: An in vitro study. Acta Pharm., 2018, 68(4), 517-524.
[http://dx.doi.org/10.2478/acph-2018-0031] [PMID: 31259708]
[28]
Huang, C.; Chen, Y.; Liu, H.; Yang, J.; Song, X.; Zhao, J.; He, N.; Zhou, C.J.; Wang, Y.; Huang, C.; Dong, Q. Celecoxib targets breast cancer stem cells by inhibiting the synthesis of prostaglandin E2 and down-regulating the Wnt pathway activity. Oncotarget, 2017, 8(70), 115254-115269.
[http://dx.doi.org/10.18632/oncotarget.23250] [PMID: 29383157]
[29]
Zhou, B.; Xiao, J.F.; Tuli, L.; Ressom, H.W. LC-MS-based metabolomics. Mol. Biosyst., 2012, 8(2), 470-481.
[http://dx.doi.org/10.1039/C1MB05350G] [PMID: 22041788]
[30]
Dahabiyeh, L.A.; Malkawi, A.K.; Wang, X.; Colak, D.; Mujamammi, A.H.; Sabi, E.M.; Li, L.; Dasouki, M. Abdel rahman, A.M. dexamethasone-induced perturbations in tissue metabolomics revealed by chemical isotope labeling LC-MS analysis. Metabolites, 2020, 10(2), 42.
[http://dx.doi.org/10.3390/metabo10020042] [PMID: 31973046]
[31]
Kumar, P.; Agarwal, A.; Singh, A.K.; Gautam, A.K.; Chakraborti, S.; Kumar, U.; Kumar, D.; Bhattacharya, B.; Panda, P.; Saha, B.; Qidwai, T.; Maity, B.; Saha, S. Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis. Regul. Toxicol. Pharmacol., 2019, 109104489
[http://dx.doi.org/10.1016/j.yrtph.2019.104489] [PMID: 31605713]
[32]
Chen, C.; Gao, J.; Wang, T.S.; Guo, C.; Yan, Y.J.; Mao, C.Y.; Gu, L.W.; Yang, Y.; Li, Z.F.; Liu, A. NMR-based metabolomic techniques identify the toxicity of emodin in HepG2 cells. Sci. Rep., 2018, 8(1), 9379.
[http://dx.doi.org/10.1038/s41598-018-27359-4] [PMID: 29925852]
[33]
Armiñán, A.; Palomino-Schätzlein, M.; Deladriere, C.; Arroyo-Crespo, J.J.; Vicente-Ruiz, S.; Vicent, M.J.; Pineda-Lucena, A. Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models. Biomateri., 2018, 162, 144-153.
[http://dx.doi.org/10.1016/j.biomaterials.2018.02.015] [PMID: 29448142]
[34]
Al-Natour, M.A.; Alazzo, A.; Ghaemmaghami, A.M.; Kim, D.H.; Alexander, C. LC-MS metabolomics comparisons of cancer cell and macrophage responses to methotrexate and polymer-encapsulated methotrexate. Int. J. Pharm. X, 2019, 1100036
[http://dx.doi.org/10.1016/j.ijpx.2019.100036] [PMID: 31993584]
[35]
Alfarouk, K.O.; Ahmed, S.B.M.; Elliott, R.L.; Benoit, A.; Alqahtani, S.S.; Ibrahim, M.E.; Bashir, A.H.H.; Alhoufie, S.T.S.; Elhassan, G.O.; Wales, C.C.; Schwartz, L.H.; Ali, H.S.; Ahmed, A.; Forde, P.F.; Devesa, J.; Cardone, R.A.; Fais, S.; Harguindey, S.; Reshkin, S.J. The pentose phosphate pathway dynamics in cancer and its dependency on intracellular pH. Metabolites, 2020, 10(7), 285.
[http://dx.doi.org/10.3390/metabo10070285] [PMID: 32664469]

Rights & Permissions Print Cite
Article Metrics
32
1
© 2024 Bentham Science Publishers | Privacy Policy