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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

Synergistic Role of Thymoquinone on Anticancer Activity of 5-Fluorouracil in Triple Negative Breast Cancer Cells

Author(s): Meiling Zheng, Zhiqiang Mei, Md. Junaid, Mousumi Tania, Junjiang Fu, Han-Chun Chen and Md. Asaduzzaman Khan*

Volume 22, Issue 6, 2022

Published on: 24 June, 2021

Page: [1111 - 1118] Pages: 8

DOI: 10.2174/1871520621666210624111613

Price: $65

Abstract

Background: Triple Negative Breast Cancer (TNBC) is considered as the most deadly subtype of breast cancer, because of heterogeneity, less treatment options and resistance to chemotherapy.

Objective: To find out an efficient chemotherapeutic options, in this study we have investigated the combined therapy of 5-Fluorouracil (5-FU) and thymoquinone (TQ) against TNBC cell lines BT-549 and MDA-MB-231.

Methods: We have tested 5-FU and TQ alone and in combination (5-FU + TQ) to observe the cellular growth, cell cycle and apoptosis status of BT-549 and MDA-MB-231 cells. Also we have measured the mRNA level expression of genes related to cell cycle and apoptosis.

Results: Experimental results suggest that both of 5-FU and TQ are effective in controlling cell growth, cell cycle and inducing apoptosis, but their combination is much more effective. 5-FU was found to be more effective in controlling cell growth, while TQ was found to be more effective in inducing apoptosis, but in both cases, their combination was most effective. TQ was found more effective in increasing and BAX/BCL-2 ratio, while 5-FU was more effective in inhibiting thymidylate synthase. They showed significant increasing effects on caspases and P53 and decreasing effect on CDK-2, where their combination was found most effective.

Conclusion: Thus, TQ and 5-FU probably showed synergistic effect on both of cell cycle and apoptosis of tested TNBC cell lines. Our study reveals that TQ can synergise 5-FU action, and increase its anticancer efficiency against TNBC cells, which might be good choice in drug development for TNBC treatment.

Keywords: Triple negative breast cancer, 5-fluorouracil, thymoquinone, apoptosis, cell cycle, combination therapy.

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[1]
Shabaruddin, F.H.; Chen, L.C.; Elliott, R.A.; Payne, K. A systematic review of utility values for chemotherapy-related adverse events. Pharmacoeconomics, 2013, 31(4), 277-288.
[http://dx.doi.org/10.1007/s40273-013-0033-x] [PMID: 23529208]
[2]
Chanan-Khan, A.A.A. Immunomodulating drugs for the treatment of cancer.Lippincott Williams & Wilkins: Baltimore, MD, USA, , 2011.
[3]
Nedeljković, M.; Damjanović, A. Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells, 2019, 8(9), 957.
[http://dx.doi.org/10.3390/cells8090957] [PMID: 31443516]
[4]
Ponce-Cusi, R.; Calaf, G.M. Apoptotic activity of 5-fluorouracil in breast cancer cells transformed by low doses of ionizing α-particle radiation. Int. J. Oncol., 2016, 48(2), 774-782.
[http://dx.doi.org/10.3892/ijo.2015.3298] [PMID: 26691280]
[5]
Heidelberger, C.; Chaudhuri, N.K.; Danneberg, P.; Mooren, D.; Griesbach, L.; Duschinsky, R.; Schnitzer, R.J.; Pleven, E.; Scheiner, J. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature, 1957, 179(4561), 663-666.
[http://dx.doi.org/10.1038/179663a0] [PMID: 13418758]
[6]
Heidelberger, C.; Danenberg, P.V.; Moran, R.G. Fluorinated pyrimidines and their nucleosides. Adv. Enzymol. Relat. Areas Mol. Biol., 1983, 54, 58-119.
[PMID: 6189380]
[7]
Gautschi, O.; Mack, P.; Gandara, D.R.; Rosell, R. Pharmacogenomics in lung cancer: Predictive biomarkers for chemotherapy.Principles and Practice of Lung Cancer: The Official Reference Text of the International Association for the Study of Lung Cancer (IASLC), 4th; Wolters Kluwer Health Adis (ESP), 2012, 683-692.
[8]
Takahashi, K.; Tanaka, M.; Inagaki, A.; Wanibuchi, H.; Izumi, Y.; Miura, K.; Nagayama, K.; Shiota, M.; Iwao, H. Establishment of a 5-fluorouracil-resistant triple-negative breast cancer cell line. Int. J. Oncol., 2013, 43(6), 1985-1991.
[http://dx.doi.org/10.3892/ijo.2013.2135] [PMID: 24126575]
[9]
O’Reilly, E.A.; Gubbins, L.; Sharma, S.; Tully, R.; Guang, M.H.; Weiner-Gorzel, K.; McCaffrey, J.; Harrison, M.; Furlong, F.; Kell, M.; McCann, A. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin., 2015, 3, 257-275.
[http://dx.doi.org/10.1016/j.bbacli.2015.03.003] [PMID: 26676166]
[10]
Mader, R.M.; Müller, M.; Steger, G.G. Resistance to 5-fluorouracil. Gen. Pharmacol., 1998, 31(5), 661-666.
[http://dx.doi.org/10.1016/S0306-3623(98)00191-8] [PMID: 9809460]
[11]
Fleischmann, J.; Kremmer, E.; Müller, S.; Sommer, P.; Kirchner, T.; Niedobitek, G.; Grässer, F.A. Expression of deoxyuridine triphosphatase (dUTPase) in colorectal tumours. Int. J. Cancer, 1999, 84(6), 614-617.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19991222)84:6<614:AID-IJC13>3.0.CO;2-P] [PMID: 10567908]
[12]
Arnold, C.N.; Goel, A.; Boland, C.R. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int. J. Cancer, 2003, 106(1), 66-73.
[http://dx.doi.org/10.1002/ijc.11176] [PMID: 12794758]
[13]
Violette, S.; Poulain, L.; Dussaulx, E.; Pepin, D.; Faussat, A.M.; Chambaz, J.; Lacorte, J.M.; Staedel, C.; Lesuffleur, T. Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int. J. Cancer, 2002, 98(4), 498-504.
[http://dx.doi.org/10.1002/ijc.10146] [PMID: 11920608]
[14]
Shi, X.; Liu, S.; Kleeff, J.; Friess, H.; Büchler, M.W. Acquired resistance of pancreatic cancer cells towards 5-Fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology, 2002, 62(4), 354-362.
[http://dx.doi.org/10.1159/000065068] [PMID: 12138244]
[15]
Asaduzzaman Khan, M.; Tania, M.; Fu, S.; Fu, J. Thymoquinone, as an anticancer molecule: From basic research to clinical investigation. Oncotarget, 2017, 8(31), 51907-51919.
[http://dx.doi.org/10.18632/oncotarget.17206] [PMID: 28881699]
[16]
Kabil, N.; Bayraktar, R.; Kahraman, N.; Mokhlis, H.A.; Calin, G.A.; Lopez-Berestein, G.; Ozpolat, B. Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer. Breast Cancer Res. Treat., 2018, 171(3), 593-605.
[http://dx.doi.org/10.1007/s10549-018-4847-2] [PMID: 29971628]
[17]
Khan, M.A.; Tania, M.; Wei, C.; Mei, Z.; Fu, S.; Cheng, J.; Xu, J.; Fu, J. Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition. Oncotarget, 2015, 6(23), 19580-19591.
[http://dx.doi.org/10.18632/oncotarget.3973] [PMID: 26023736]
[18]
Akter, Z.; Ahmed, F.R.; Tania, M.; Khan, M.A. Targeting inflammatory mediators: An anticancer mechanism of thymoquinone action. Curr. Med. Chem., 2021, 28(1), 80-92.
[http://dx.doi.org/10.2174/0929867326666191011143642] [PMID: 31604405]
[19]
Junaid, M.; Akter, Y.; Afrose, S.S.; Tania, M.; Khan, M.A. Biological role of akt and regulation of akt signaling pathway by thymoquinone: Perspectives in cancer therapeutics. Mini Rev. Med. Chem., 21(3), 288-301.
[20]
Kabil, N.N.; Bayraktar, R.; Kahraman, N.; Ozpolat, B. Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, New Orleans, LA, USAApril 16-20, 2016.
[21]
Ndreshkjana, B.; Çapci, A.; Klein, V.; Chanvorachote, P.; Muenzner, J.K.; Huebner, K.; Steinmann, S.; Erlenbach-Wuensch, K.; Geppert, C.I.; Agaimy, A.; Ballout, F.; El-Baba, C.; Gali-Muhtasib, H.; Roehe, A.V.; Hartmann, A.; Tsogoeva, S.B.; Schneider-Stock, R. Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells. Cell Death Dis., 2019, 10(6), 379.
[http://dx.doi.org/10.1038/s41419-019-1611-4] [PMID: 31097715]
[22]
Bashmail, H.A.; Alamoudi, A.A.; Noorwali, A.; Hegazy, G.A.; AJabnoor, G.; Choudhry, H.; Al-Abd, A.M. Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities. Sci. Rep., 2018, 8(1), 11674.
[http://dx.doi.org/10.1038/s41598-018-30046-z] [PMID: 30076320]
[23]
Singh, S.K.; Apata, T.; Gordetsky, J.B.; Singh, R. Docetaxel combined with thymoquinone induces apoptosis in prostate cancer cells via inhibition of the pi3k/akt signaling pathway. Cancers (Basel), 2019, 11(9), 1390.
[http://dx.doi.org/10.3390/cancers11091390] [PMID: 31540423]
[24]
Alaufi, O.M.; Noorwali, A.; Zahran, F.; Al-Abd, A.M.; Al-Attas, S. Cytotoxicity of thymoquinone alone or in combination with cisplatin (CDDP) against oral squamous cell carcinoma In vitro. Sci. Rep., 2017, 7(1), 13131.
[http://dx.doi.org/10.1038/s41598-017-13357-5] [PMID: 29030590]
[25]
Şakalar, Ç.; İzgi, K.; İskender, B.; Sezen, S.; Aksu, H.; Çakır, M.; Kurt, B.; Turan, A.; Canatan, H. The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer. Tumour Biol., 2016, 37(4), 4467-4477.
[http://dx.doi.org/10.1007/s13277-015-4307-0] [PMID: 26500095]
[26]
Foidart, P.; Yip, C.; Radermacher, J.; Blacher, S.; Lienard, M.; Montero-Ruiz, L.; Maquoi, E.; Montaudon, E.; Château-Joubert, S.; Collignon, J.; Coibion, M.; Jossa, V.; Marangoni, E.; Noël, A.; Sounni, N.E.; Jerusalem, G. Expression of MT4-MMP, EGFR, and RB in triple-negative breast cancer strongly sensitizes tumors to erlotinib and palbociclib combination therapy. Clin. Cancer Res., 2019, 25(6), 1838-1850.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1880] [PMID: 30504427]
[27]
Lee, A.; Djamgoz, M.B.A. Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treat. Rev., 2018, 62, 110-122.
[http://dx.doi.org/10.1016/j.ctrv.2017.11.003] [PMID: 29202431]
[28]
Chalakur-Ramireddy, N.K.R.; Pakala, S.B. Combined drug therapeutic strategies for the effective treatment of Triple Negative Breast Cancer. Biosci. Rep., 2018, 38(1), BSR20171357.
[http://dx.doi.org/10.1042/BSR20171357] [PMID: 29298879]
[29]
Foucquier, J.; Guedj, M. Analysis of drug combinations: Current methodological landscape. Pharmacol. Res. Perspect., 2015, 3(3), e00149.
[http://dx.doi.org/10.1002/prp2.149] [PMID: 26171228]
[30]
Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 2006, 58(3), 621-681.
[http://dx.doi.org/10.1124/pr.58.3.10] [PMID: 16968952]
[31]
Ding, Y.; Su, S.; Zhang, R.; Shao, L.; Zhang, Y.; Wang, B.; Li, Y.; Chen, L.; Yu, Q.; Wu, Y.; Nie, G. Precision combination therapy for triple negative breast cancer via biomimetic polydopamine polymer core-shell nanostructures. Biomaterials, 2017, 113, 243-252.
[http://dx.doi.org/10.1016/j.biomaterials.2016.10.053] [PMID: 27829203]
[32]
Lei, X.; Lv, X.; Liu, M.; Yang, Z.; Ji, M.; Guo, X.; Dong, W. Thymoquinone inhibits growth and augments 5-fluorouracil-induced apoptosis in gastric cancer cells both In vitro and in vivo. Biochem. Biophys. Res. Commun., 2012, 417(2), 864-868.
[http://dx.doi.org/10.1016/j.bbrc.2011.12.063] [PMID: 22206670]
[33]
Kensara, O.A.; El-Shemi, A.G.; Mohamed, A.M.; Refaat, B.; Idris, S.; Ahmad, J. Thymoquinone subdues tumor growth and potentiates the chemopreventive effect of 5-fluorouracil on the early stages of colorectal carcinogenesis in rats. Drug Des. Devel. Ther., 2016, 10, 2239-2253.
[http://dx.doi.org/10.2147/DDDT.S109721] [PMID: 27468227]
[34]
Rooney, S.; Ryan, M.F. Modes of action of alpha-hederin and thymoquinone, active constituents of Nigella sativa, against HEp-2 cancer cells. Anticancer Res., 2005, 25(6B), 4255-4259.
[PMID: 16309225]
[35]
Shoieb, A.M.; Elgayyar, M.; Dudrick, P.S.; Bell, J.L.; Tithof, P.K. In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. Int. J. Oncol., 2003, 22(1), 107-113.
[http://dx.doi.org/10.3892/ijo.22.1.107] [PMID: 12469192]
[36]
Sutton, K.M.; Greenshields, A.L.; Hoskin, D.W. Thymoquinone, a bioactive component of black caraway seeds, causes G1 phase cell cycle arrest and apoptosis in triple-negative breast cancer cells with mutant p53. Nutr. Cancer, 2014, 66(3), 408-418.
[http://dx.doi.org/10.1080/01635581.2013.878739] [PMID: 24579801]
[37]
Khan, M.A.; Zheng, M.; Fu, J. Epigenetic modification of oncogenes or tumor suppressor genes by thymoquinone in triple negative breast cancer. Proceedings of the American Association for Cancer Research Annual Meeting 2019, Atlanta, GA, USAMarch 29-April 3, 2019.
[38]
Ünal, T.D.; Hamurcu, Z.; Delibaşı, N.; Çınar, V.; Güler, A.; Gökçe, S.; Nurdinov, N.; Ozpolat, B. Thymoquinone inhibits proliferation and migration of mda-mb-231 triple negative breast cancer cells by suppressing autophagy, beclin-1 and lc3. Anticancer. Agents Med. Chem., 2021, 21(3), 355-364.
[http://dx.doi.org/10.2174/1871520620666200807221047] [PMID: 32767958]
[39]
Abdelfadil, E.; Cheng, Y.H.; Bau, D.T.; Ting, W.J.; Chen, L.M.; Hsu, H.H.; Lin, Y.M.; Chen, R.J.; Tsai, F.J.; Tsai, C.H.; Huang, C.Y. Thymoquinone induces apoptosis in oral cancer cells through p38β inhibition. Am. J. Chin. Med., 2013, 41(3), 683-696.
[http://dx.doi.org/10.1142/S0192415X1350047X] [PMID: 23711149]
[40]
Fahad Ullah, M. Breast cancer: Current perspectives on the disease status. Adv. Exp. Med. Biol., 2019, 1152, 51-64.
[http://dx.doi.org/10.1007/978-3-030-20301-6_4] [PMID: 31456179]
[41]
Su, P.; Ahmad, B.; Zou, K.; Zou, L. β-elemene enhances the chemotherapeutic effect of 5-fluorouracil in triple-negative breast cancer via pi3k/akt, raf-mek-erk, and nf-κb signaling pathways. OncoTargets Ther., 2020, 13, 5207-5222.
[http://dx.doi.org/10.2147/OTT.S242820] [PMID: 32606741]
[42]
Joensuu, H.; Gligorov, J. Adjuvant treatments for triple-negative breast cancers. Ann. Oncol., 2012, 23(Suppl. 6), vi40-vi45.
[http://dx.doi.org/10.1093/annonc/mds194] [PMID: 23012301]
[43]
Effenberger-Neidnicht, K.; Schobert, R. Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother. Pharmacol., 2011, 67(4), 867-874.
[http://dx.doi.org/10.1007/s00280-010-1386-x] [PMID: 20582416]
[44]
Jafri, S.H.; Glass, J.; Shi, R.; Zhang, S.; Prince, M.; Kleiner-Hancock, H. Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J. Exp. Clin. Cancer Res., 2010, 29(1), 87.
[http://dx.doi.org/10.1186/1756-9966-29-87] [PMID: 20594324]

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