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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Targeting Inflammatory Mediators: An Anticancer Mechanism of Thymoquinone Action

Author(s): Zakia Akter, Faiza Rafa Ahmed, Mousumi Tania and Md. Asaduzzaman Khan*

Volume 28, Issue 1, 2021

Published on: 11 October, 2019

Page: [80 - 92] Pages: 13

DOI: 10.2174/0929867326666191011143642

Price: $65

Abstract

Background: Thymoquinone is a promising anticancer molecule, the chemopreventive role of which is well-known at least in vitro and in the animal model. In this review article, we focused on the anti-inflammatory activities of thymoquinone in cancer cells.

Method: Research data on inflammation, cancer and thymoquinone were acquired from PubMed, Scopus, Web of Science and Google Scholar. We reviewed papers published since the mid of the last century, and the most cited papers of the last ten years.

Results: Studies indicate that thymoquinone possesses immunomodulatory activities, in addition to its chemopreventive role, as thymoquinone can target and modulate inflammatory molecules, like nuclear factor kappa B (NF-κβ), interleukins, tumor necrosis factor-α (TNF-α), and certain growth factors. As chronic inflammation plays an important role in cancer development, controlling inflammatory pathways is an important mechanism of an anticancer molecule, and modulation of inflammatory pathways might be one of the key mechanisms of thymoquinone’s anticancer activities.

Conclusion: This article reviewed the role of inflammation on cancer development, and the action of thymoquinone on inflammatory molecules, which have been proved in vitro and in vivo. Much attention is required for studying the role of thymoquinone in immunotherapeutics and developing this molecule as a future anticancer drug.

Keywords: Cancer, Thymoquinone, Immunotherapeutics, Inflammatory modulators, NF-κβ, uncontrolled proliferation.

« Previous
[1]
Ma, X.; Yu, H. Global burden of cancer. Yale J. Biol. Med., 2006, 79(3-4), 85-94.
[PMID: 17940618]
[2]
World Health Organization Cancer (Fact sheet) 2018, 12, Available at: https://www.who.int/news-room/fact-sheets/detail/cancer (Accessed date: August 19, 2019).
[3]
Miller, K.D.; Nogueira, L.; Mariotto, A.B.; Rowland, J.H.; Yabroff, K.R.; Alfano, C.M.; Jemal, A.; Kramer, J.L.; Siegel, R.L. Cancer treatment and survivorship statistics. CA Cancer J. Clin., 2019, 69(5), 363-385.
[http://dx.doi.org/10.3322/caac.21565] [PMID: 31184787]
[4]
Elinav, E.; Nowarski, R.; Thaiss, C.A.; Hu, B.; Jin, C.; Flavell, R.A. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer, 2013, 13(11), 759-771.
[http://dx.doi.org/10.1038/nrc3611] [PMID: 24154716]
[5]
Balkwill, F.; Mantovani, A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357(9255), 539-545.
[http://dx.doi.org/10.1016/S0140-6736(00)04046-0] [PMID: 11229684]
[6]
Hussain, S.P.; Harris, C.C. Inflammation and cancer: an ancient link with novel potentials. Int. J. Cancer, 2007, 121(11), 2373-2380.
[http://dx.doi.org/10.1002/ijc.23173] [PMID: 17893866]
[7]
Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature, 2002, 420(6917), 860-867.
[http://dx.doi.org/10.1038/nature01322] [PMID: 12490959]
[8]
Zhu, Z.; Zhong, S.; Shen, Z. Targeting the inflammatory pathways to enhance chemotherapy of cancer. Cancer Biol. Ther., 2011, 12(2), 95-105.
[http://dx.doi.org/10.4161/cbt.12.2.15952] [PMID: 21623164]
[9]
Qu, X.; Tang, Y.; Hua, S. Immunological approaches towards cancer and inflammation: a cross talk. Front. Immunol., 2018, 9, 563.
[http://dx.doi.org/10.3389/fimmu.2018.00563] [PMID: 29662489]
[10]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70(3), 461-477.
[http://dx.doi.org/10.1021/np068054v] [PMID: 17309302]
[11]
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]
[12]
Mahmoud, Y.K.; Abdelrazek, H.M.A. Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy. Biomed. Pharmacother., 2019, 115108783
[http://dx.doi.org/10.1016/j.biopha.2019.108783] [PMID: 31060003]
[13]
Kundu, J.K.; Surh, Y. J. Inflammation: gearing the journey to cancer. Mutat. Res., 2008, 659(1-2), 15-30.
[http://dx.doi.org/10.1016/j.mrrev.2008.03.002] [PMID: 18485806]
[14]
Bartsch, H.; Nair, J. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch. Surg., 2006, 391(5), 499-510.
[http://dx.doi.org/10.1007/s00423-006-0073-1] [PMID: 16909291]
[15]
Schetter, A.J.; Heegaard, N.H.; Harris, C.C. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 2010, 31(1), 37-49.
[http://dx.doi.org/10.1093/carcin/bgp272] [PMID: 19955394]
[16]
Pikarsky, E.; Porat, R.M.; Stein, I.; Abramovitch, R.; Amit, S.; Kasem, S.; Gutkovich-Pyest, E.; Urieli-Shoval, S.; Galun, E.; Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature, 2004, 431(7007), 461-466.
[http://dx.doi.org/10.1038/nature02924] [PMID: 15329734]
[17]
Shen, H.M.; Tergaonkar, V. NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis, 2009, 14(4), 348-363.
[http://dx.doi.org/10.1007/s10495-009-0315-0] [PMID: 19212815]
[18]
Djavaheri-Mergny, M.; Amelotti, M.; Mathieu, J.; Besançon, F.; Bauvy, C.; Souquère, S.; Pierron, G.; Codogno, P. NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J. Biol. Chem., 2006, 281(41), 30373-30382.
[http://dx.doi.org/10.1074/jbc.M602097200] [PMID: 16857678]
[19]
Hernanz, R.; Briones, A.M.; Salaices, M.; Alonso, M.J. New roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. Clin. Sci. (Lond.), 2014, 126(2), 111-121.
[http://dx.doi.org/10.1042/CS20120651] [PMID: 24059588]
[20]
Helbig, G.; Christopherson, K.W. II.; Bhat-Nakshatri, P.; Kumar, S.; Kishimoto, H.; Miller, K.D.; Broxmeyer, H.E.; Nakshatri, H. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J. Biol. Chem., 2003, 278(24), 21631-21638.
[http://dx.doi.org/10.1074/jbc.M300609200] [PMID: 12690099]
[21]
Tergaonkar, V. NFkappaB pathway: a good signaling paradigm and therapeutic target. Int. J. Biochem. Cell Biol., 2006, 38(10), 1647-1653.
[http://dx.doi.org/10.1016/j.biocel.2006.03.023] [PMID: 16766221]
[22]
Ren, J.L.; Pan, J.S.; Lu, Y.P.; Sun, P.; Han, J. Inflammatory signaling and cellular senescence. Cell. Signal., 2009, 21(3), 378-383.
[http://dx.doi.org/10.1016/j.cellsig.2008.10.011] [PMID: 18992324]
[23]
Pan, J.S.; Hong, M.Z.; Ren, J.L. Reactive oxygen species: a double-edged sword in oncogenesis. World J. Gastroenterol., 2009, 15(14), 1702-1707.
[http://dx.doi.org/10.3748/wjg.15.1702] [PMID: 19360913]
[24]
Meira, L.B.; Bugni, J.M.; Green, S.L.; Lee, C.W.; Pang, B.; Borenshtein, D.; Rickman, B.H.; Rogers, A.B.; Moroski-Erkul, C.A.; McFaline, J.L.; Schauer, D.B.; Dedon, P.C.; Fox, J.G.; Samson, L.D. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J. Clin. Invest., 2008, 118(7), 2516-2525.
[http://dx.doi.org/10.1172/JCI35073] [PMID: 18521188]
[25]
Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science, 2008, 320(5876), 661-664.
[http://dx.doi.org/10.1126/science.1156906] [PMID: 18388260]
[26]
Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer, 2009, 9(5), 361-371.
[http://dx.doi.org/10.1038/nrc2628] [PMID: 19343034]
[27]
Pasparakis, M.; Alexopoulou, L.; Episkopou, V.; Kollias, G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med., 1996, 184(4), 1397-1411.
[http://dx.doi.org/10.1084/jem.184.4.1397] [PMID: 8879212]
[28]
Ancrile, B.; Lim, K.H.; Counter, C.M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev., 2007, 21(14), 1714-1719.
[http://dx.doi.org/10.1101/gad.1549407] [PMID: 17639077]
[29]
Gyamfi, J.; Eom, M.; Koo, J.S.; Choi, J. Multifaceted roles of interleukin-6 in adipocyte-breast cancer cell interaction. Transl. Oncol., 2018, 11(2), 275-285.
[http://dx.doi.org/10.1016/j.tranon.2017.12.009] [PMID: 29413760]
[30]
Razidlo, G.L.; Burton, K.M.; McNiven, M.A. Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J. Biol. Chem., 2018, 293(28), 11143-11153.
[http://dx.doi.org/10.1074/jbc.RA118.003276] [PMID: 29853638]
[31]
Schneider, M.R.; Hoeflich, A.; Fischer, J.R.; Wolf, E.; Sordat, B.; Lahm, H. Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells. Cancer Lett., 2000, 151(1), 31-38.
[http://dx.doi.org/10.1016/S0304-3835(99)00401-2] [PMID: 10766420]
[32]
Cozen, W.; Gill, P.S.; Ingles, S.A.; Masood, R.; Martínez-Maza, O.; Cockburn, M.G.; Gauderman, W.J.; Pike, M.C.; Bernstein, L.; Nathwani, B.N.; Salam, M.T.; Danley, K.L.; Wang, W.; Gage, J.; Gundell-Miller, S.; Mack, T.M. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood, 2004, 103(8), 3216-3221.
[http://dx.doi.org/10.1182/blood-2003-08-2860] [PMID: 15070705]
[33]
Kai, H.; Kitadai, Y.; Kodama, M.; Cho, S.; Kuroda, T.; Ito, M.; Tanaka, S.; Ohmoto, Y.; Chayama, K. Involvement of proinflammatory cytokines IL-1beta and IL-6 in progression of human gastric carcinoma. Anticancer Res., 2005, 25(2A), 709-713.
[PMID: 15868900]
[34]
Genrich, G.; Kruppa, M.; Lenk, L.; Helm, O.; Broich, A.; Freitag-Wolf, S.; Röcken, C.; Sipos, B.; Schäfer, H.; Sebens, S. The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1. BMC Cancer, 2016, 16, 155.
[http://dx.doi.org/10.1186/s12885-016-2191-7] [PMID: 26915435]
[35]
Mosser, D.M.; Zhang, X. Interleukin-10: new perspectives on an old cytokine. Immunol. Rev., 2008, 226, 205-218.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00706.x] [PMID: 19161426]
[36]
Chehl, N.; Chipitsyna, G.; Gong, Q.; Yeo, C.J.; Arafat, H.A. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford), 2009, 11(5), 373-381.
[http://dx.doi.org/10.1111/j.1477-2574.2009.00059.x] [PMID: 19768141]
[37]
Todoric, J.; Antonucci, L.; Karin, M. Targeting inflammation in cancer prevention and therapy. Cancer Prev. Res. (Phila.), 2016, 9(12), 895-905.
[http://dx.doi.org/10.1158/1940-6207.CAPR-16-0209] [PMID: 27913448]
[38]
Aggarwal, B.B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol., 2003, 3(9), 745-756.
[http://dx.doi.org/10.1038/nri1184] [PMID: 12949498]
[39]
Karin, M.; Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-[κ]B activity. Annu. Rev. Immunol., 2000, 18, 621-663.
[http://dx.doi.org/10.1146/annurev.immunol.18.1.621] [PMID: 10837071]
[40]
Matsushima, A.; Kaisho, T.; Rennert, P.D.; Nakano, H.; Kurosawa, K.; Uchida, D.; Takeda, K.; Akira, S.; Matsumoto, M. Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase α in NF-kappaB activation through lymphotoxin β receptor, but not through tumor necrosis factor receptor I. J. Exp. Med., 2001, 193(5), 631-636.
[http://dx.doi.org/10.1084/jem.193.5.631] [PMID: 11238593]
[41]
Mitchell, J.P.; Carmody, R.J. NF-κB and the Transcriptional control of inflammation. Int. Rev. Cell Mol. Biol., 2018, 335, 41-84.
[http://dx.doi.org/10.1016/bs.ircmb.2017.07.007] [PMID: 29305014]
[42]
Ben-Neriah, Y.; Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol., 2011, 12(8), 715-723.
[http://dx.doi.org/10.1038/ni.2060] [PMID: 21772280]
[43]
Ahn, K.S.; Aggarwal, B.B. Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann. N. Y. Acad. Sci., 2005, 1056, 218-233.
[http://dx.doi.org/10.1196/annals.1352.026] [PMID: 16387690]
[44]
Akiba, J.; Yano, H.; Ogasawara, S.; Higaki, K.; Kojiro, M. Expression and function of interleukin-8 in human hepatocellular carcinoma. Int. J. Oncol., 2001, 18(2), 257-264.
[http://dx.doi.org/10.3892/ijo.18.2.257] [PMID: 11172590]
[45]
Ashour, A.E.; Abd-Allah, A.R.; Korashy, H.M.; Attia, S.M.; Alzahrani, A.Z.; Saquib, Q.; Bakheet, S.A.; Abdel-Hamied, H.E.; Jamal, S.; Rishi, A.K. Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis. Mol. Cell. Biochem., 2014, 389(1-2), 85-98.
[http://dx.doi.org/10.1007/s11010-013-1930-1] [PMID: 24399465]
[46]
Xu, D.; Ma, Y.; Zhao, B.; Li, S.; Zhang, Y.; Pan, S.; Wu, Y.; Wang, J.; Wang, D.; Pan, H.; Liu, L.; Jiang, H. Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-κB pathways in human cholangiocarcinomas both in vitro and in vivo. Oncol. Rep., 2014, 31(5), 2063-2070.
[http://dx.doi.org/10.3892/or.2014.3059] [PMID: 24603952]
[47]
Wu, Z.H.; Chen, Z.; Shen, Y.; Huang, L.L.; Jiang, P. [Antimetastasis effect of thymoquinone on human pancreatic cancer] Yao Xue Xue Bao, 2011, 46(8), 910-914.
[PMID: 22007514]
[48]
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, 87.
[http://dx.doi.org/10.1186/1756-9966-29-87] [PMID: 20594324]
[49]
Sakalar, C.; Yuruk, M.; Kaya, T.; Aytekin, M.; Kuk, S.; Canatan, H. Pronounced transcriptional regulation of apoptotic and TNF-NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells. Mol. Cell. Biochem., 2013, 383(1-2), 243-251.
[http://dx.doi.org/10.1007/s11010-013-1772-x] [PMID: 23943306]
[50]
Peng, L.; Liu, A.; Shen, Y.; Xu, H.Z.; Yang, S.Z.; Ying, X.Z.; Liao, W.; Liu, H.X.; Lin, Z.Q.; Chen, Q.Y.; Cheng, S.W.; Shen, W.D. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol. Rep., 2013, 29(2), 571-578.
[http://dx.doi.org/10.3892/or.2012.2165] [PMID: 23232982]
[51]
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]
[52]
Chen, M.C.; Lee, N.H.; Hsu, H.H.; Ho, T.J.; Tu, C.C.; Chen, R.J.; Lin, Y.M.; Viswanadha, V.P.; Kuo, W.W.; Huang, C.Y. Inhibition of NF-κB and metastasis in irinotecan (CPT-11)-resistant LoVo colon cancer cells by thymoquinone via JNK and p38. Environ. Toxicol., 2017, 32(2), 669-678.
[http://dx.doi.org/10.1002/tox.22268] [PMID: 27060453]
[53]
Ashour, A.E.; Ahmed, A.F.; Kumar, A.; Zoheir, K.M.; Aboul-Soud, M.A.; Ahmad, S.F.; Attia, S.M.; Abd-Allah, A.R.; Cheryan, V.T.; Rishi, A.K. Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-κB signaling and IL-8 expression. Mol. Cell. Biochem., 2016, 416(1-2), 141-155.
[http://dx.doi.org/10.1007/s11010-016-2703-4] [PMID: 27084536]
[54]
Popa, C.; Netea, M.G.; van Riel, P.L.; van der Meer, J.W.; Stalenhoef, A.F. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J. Lipid Res., 2007, 48(4), 751-762.
[http://dx.doi.org/10.1194/jlr.R600021-JLR200] [PMID: 17202130]
[55]
Sethi, G.; Sung, B.; Aggarwal, B.B. TNF: a master switch for inflammation to cancer. Front. Biosci., 2008, 13, 5094-5107.
[http://dx.doi.org/10.2741/3066] [PMID: 18508572]
[56]
Kabel, A.M.; El-Rashidy, M.A.; Omar, M.S. Ameliorative potential of tamoxifen/thymoquinone combination in patients with breast cancer: a biochemical and immunohistochemical study. J. Cancer Sci. Res., 2016, 1, 102.
[57]
Sethi, G.; Ahn, K.S.; Aggarwal, B.B. Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol. Cancer Res., 2008, 6(6), 1059-1070.
[http://dx.doi.org/10.1158/1541-7786.MCR-07-2088] [PMID: 18567808]
[58]
Bickel, M. The role of interleukin-8 in inflammation and mechanisms of regulation. J. Periodontol., 1993, 64(5)(Suppl.), 456-460.
[PMID: 8315568]
[59]
Brat, D.J.; Bellail, A.C.; Van Meir, E.G. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol., 2005, 7(2), 122-133.
[http://dx.doi.org/10.1215/S1152851704001061] [PMID: 15831231]
[60]
Cheng, G.Z.; Park, S.; Shu, S.; He, L.; Kong, W.; Zhang, W.; Yuan, Z.; Wang, L.H.; Cheng, J.Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets, 2008, 8(1), 2-6.
[http://dx.doi.org/10.2174/156800908783497159] [PMID: 18288938]
[61]
Nguyen, D.P.; Li, J.; Tewari, A.K. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int., 2014, 113(6), 986-992.
[http://dx.doi.org/10.1111/bju.12452] [PMID: 24053309]
[62]
Al-Trad, B.; Al-Zoubi, M.; Qar, J.; Al-Batayneh, K.; Hussien, E.; Muhaidat, R.; Aljabali, A.; Alkhateeb, H.; Al Omari, G. Inhibitory effect of thymoquinone on testosterone-induced benign prostatic hyperplasia in Wistar rats. Phytother. Res., 2017, 31(12), 1910-1915.
[http://dx.doi.org/10.1002/ptr.5936] [PMID: 28960541]
[63]
Miliani, M.; Nouar, M.; Paris, O.; Lefranc, G.; Mennechet, F.; Aribi, M. Thymoquinone potently enhances the activities of classically activated macrophages pulsed with necrotic jurkat cell lysates and the production of antitumor Th1-/M1-related cytokines. J. Interferon Cytokine Res., 2018, 38(12), 539-551.
[http://dx.doi.org/10.1089/jir.2018.0010] [PMID: 30422744]
[64]
Anderson, G.D.; Hauser, S.D.; McGarity, K.L.; Bremer, M.E.; Isakson, P.C.; Gregory, S.A. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J. Clin. Invest., 1996, 97(11), 2672-2679.
[http://dx.doi.org/10.1172/JCI118717] [PMID: 8647962]
[65]
Kim, Y.B.; Kim, G.E.; Cho, N.H.; Pyo, H.R.; Shim, S.J.; Chang, S.K.; Park, H.C.; Suh, C.O.; Park, T.K.; Kim, B.S. Overexpression of cyclooxygenase-2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy. Cancer, 2002, 95(3), 531-539.
[http://dx.doi.org/10.1002/cncr.10684] [PMID: 12209745]
[66]
Pai, R.; Soreghan, B.; Szabo, I.L.; Pavelka, M.; Baatar, D.; Tarnawski, A.S. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med., 2002, 8(3), 289-293.
[http://dx.doi.org/10.1038/nm0302-289] [PMID: 11875501]
[67]
Steinbach, G.; Lynch, P.M.; Phillips, R.K.; Wallace, M.H.; Hawk, E.; Gordon, G.B.; Wakabayashi, N.; Saunders, B.; Shen, Y.; Fujimura, T.; Su, L.K.; Levin, B.; Godio, L.; Patterson, S.; Rodriguez-Bigas, M.A.; Jester, S.L.; King, K.L.; Schumacher, M.; Abbruzzese, J.; DuBois, R.N.; Hittelman, W.N.; Zimmerman, S.; Sherman, J.W.; Kelloff, G. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med., 2000, 342(26), 1946-1952.
[http://dx.doi.org/10.1056/NEJM200006293422603] [PMID: 10874062]
[68]
Hsu, H.H.; Chen, M.C.; Day, C.H.; Lin, Y.M.; Li, S.Y.; Tu, C.C.; Padma, V.V.; Shih, H.N.; Kuo, W.W.; Huang, C.Y. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation. World J. Gastroenterol., 2017, 23(7), 1171-1179.
[http://dx.doi.org/10.3748/wjg.v23.i7.1171] [PMID: 28275297]
[69]
Marsik, P.; Kokoska, L.; Landa, P.; Nepovim, A.; Soudek, P.; Vanek, T. In vitro inhibitory effects of thymol and quinones of Nigella sativa seeds on cyclooxygenase-1- and -2-catalyzed prostaglandin E2 biosyntheses. Planta Med., 2005, 71(8), 739-742.
[http://dx.doi.org/10.1055/s-2005-871288] [PMID: 16142638]
[70]
Brierley, M.M.; Fish, E.N. Stats: multifaceted regulators of transcription. J. Interferon Cytokine Res., 2005, 25(12), 733-744.
[http://dx.doi.org/10.1089/jir.2005.25.733] [PMID: 16375601]
[71]
Bowman, T.; Garcia, R.; Turkson, J.; Jove, R. STATs in oncogenesis. Oncogene, 2000, 19(21), 2474-2488.
[http://dx.doi.org/10.1038/sj.onc.1203527] [PMID: 10851046]
[72]
Yu, H.; Jove, R. The STATs of cancer--new molecular targets come of age. Nat. Rev. Cancer, 2004, 4(2), 97-105.
[http://dx.doi.org/10.1038/nrc1275] [PMID: 14964307]
[73]
Yue, P.; Turkson, J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Investig. Drugs, 2009, 18(1), 45-56.
[http://dx.doi.org/10.1517/13543780802565791] [PMID: 19053881]
[74]
Kaplan, M.H. STAT signaling in inflammation. JAK-STAT, 2013, 2(1)e24198
[http://dx.doi.org/10.4161/jkst.24198] [PMID: 24058801]
[75]
Zhu, W.Q.; Wang, J.; Guo, X.F.; Liu, Z.; Dong, W.G. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J. Gastroenterol., 2016, 22(16), 4149-4159.
[http://dx.doi.org/10.3748/wjg.v22.i16.4149] [PMID: 27122665]
[76]
Li, F.; Rajendran, P.; Sethi, G. Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br. J. Pharmacol., 2010, 161(3), 541-554.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00874.x] [PMID: 20880395]
[77]
Ferrara, N.; Henzel, W.J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun., 1989, 161(2), 851-858.
[http://dx.doi.org/10.1016/0006-291X(89)92678-8] [PMID: 2735925]
[78]
Pepper, M.S.; Ferrara, N.; Orci, L.; Montesano, R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem. Biophys. Res. Commun., 1992, 189(2), 824-831.
[http://dx.doi.org/10.1016/0006-291X(92)92277-5] [PMID: 1281999]
[79]
Waldner, M.J.; Wirtz, S.; Jefremow, A.; Warntjen, M.; Neufert, C.; Atreya, R.; Becker, C.; Weigmann, B.; Vieth, M.; Rose-John, S.; Neurath, M.F. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J. Exp. Med., 2010, 207(13), 2855-2868.
[http://dx.doi.org/10.1084/jem.20100438] [PMID: 21098094]
[80]
Asfour, W.; Almadi, S.; Haffar, L. Thymoquinone suppresses cellular proliferation, inhibits VEGF production and obstructs tumor progression and invasion in the rat Model of DMH-induced colon carcinogenesis. Pharmacol. Pharm., 2013, 4, 7-17.
[http://dx.doi.org/10.4236/pp.2013.41002]
[81]
Paramasivam, A.; Raghunandhakumar, S.; Sambantham, S.; Anandan, B.; Rajiv, R.; Priyadharsini, J.V.; Jayaraman, G. In vitro anticancer and anti-angiogenic effects of thymoquinone in mouse neuroblastoma cells (Neuro-2a). Biomed. Prevent. Nutri., 2012, 2, 283-286.
[http://dx.doi.org/10.1016/j.bionut.2012.04.004]
[82]
ElKhoely, A.; Hafez, H.F.; Ashmawy, A.M.; Badary, O.; Abdelaziz, A.; Mostafa, A.; Shouman, S.A. Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives. J. Nat. Med., 2015, 69(3), 313-323.
[http://dx.doi.org/10.1007/s11418-015-0895-7] [PMID: 25796541]
[83]
Salem, M.L.; Alenzi, F.Q.; Attia, W.Y. Thymoquinone, the active ingredient of Nigella sativa seeds, enhances survival and activity of antigen-specific CD8-positive T cells in vitro. Br. J. Biomed. Sci., 2011, 68(3), 131-137.
[http://dx.doi.org/10.1080/09674845.2011.11730340] [PMID: 21950205]
[84]
Schroder, K.; Hertzog, P.J.; Ravasi, T.; Hume, D.A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol., 2004, 75(2), 163-189.
[http://dx.doi.org/10.1189/jlb.0603252] [PMID: 14525967]
[85]
Aziz, N.; Son, Y.J.; Cho, J.Y. Thymoquinone Suppresses IRF-3-Mediated Expression of Type I Interferons via Suppression of TBK1. Int. J. Mol. Sci., 2018, 19(5)E1355
[http://dx.doi.org/10.3390/ijms19051355] [PMID: 29751576]
[86]
Ammar, S.M.; Gameil, N.M.; Shawky, N.M.; Nader, M.A. Comparative evaluation of anti-inflammatory properties of thymoquinone and curcumin using an asthmatic murine model. Int. Immunopharmacol., 2011, 11(12), 2232-2236.
[http://dx.doi.org/10.1016/j.intimp.2011.10.013] [PMID: 22051975]
[87]
Gruber, B.L.; Marchese, M.J.; Kew, R.R. Transforming growth factor-beta 1 mediates mast cell chemotaxis. J. Immunol., 1994, 152(12), 5860-5867.
[PMID: 7515916]
[88]
Vaillancourt, F.; Silva, P.; Shi, Q.; Fahmi, H.; Fernandes, J.C.; Benderdour, M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. J. Cell. Biochem., 2011, 112(1), 107-117.
[http://dx.doi.org/10.1002/jcb.22884] [PMID: 20872780]
[89]
El-Mahmoudy, A.; Matsuyama, H.; Borgan, M.A.; Shimizu, Y.; El-Sayed, M.G.; Minamoto, N.; Takewaki, T. Thymoquinone suppresses expression of inducible nitric oxide synthase in rat macrophages. Int. Immunopharmacol., 2002, 2(11), 1603-1611.
[http://dx.doi.org/10.1016/S1567-5769(02)00139-X] [PMID: 12433061]
[90]
Cobourne-Duval, M.K.; Taka, E.; Mendonca, P.; Soliman, K.F.A. Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells. J. Neuroimmunol., 2018, 320, 87-97.
[http://dx.doi.org/10.1016/j.jneuroim.2018.04.018] [PMID: 29759145]
[91]
Wraith, D.C. The Future of immunotherapy: a 20-year perspective. Front. Immunol., 2017, 8, 1668.
[http://dx.doi.org/10.3389/fimmu.2017.01668] [PMID: 29234325]
[92]
Zhang, H.; Chen, J. Current status and future directions of cancer immunotherapy. J. Cancer, 2018, 9(10), 1773-1781.
[http://dx.doi.org/10.7150/jca.24577] [PMID: 29805703]
[93]
Whiteside, T.L.; Demaria, S.; Rodriguez-Ruiz, M.E.; Zarour, H.M.; Melero, I. Emerging opportunities and challenges in cancer immunotherapy. Clin. Cancer Res., 2016, 22(8), 1845-1855.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0049] [PMID: 27084738]
[94]
Tang, H.; Qiao, J.; Fu, Y.X. Immunotherapy and tumor microenvironment. Cancer Lett., 2016, 370(1), 85-90.
[http://dx.doi.org/10.1016/j.canlet.2015.10.009] [PMID: 26477683]
[95]
Cancer Research Institute. Cancer Clinical Trials. 2019. Available at: https://www.cancerresearch.org/patients/clinical-trials (Accessed date: August 19, 2019).
[96]
Fischer, K. FDA approves first immunotherapy drug for triple negative breast cancer. Health News., 2019. Available from:, https://www.healthline.com/health-news/fda-approves-first-immunotherapy-drug-for-triple-negative-breast-cancer
[97]
Schmid, P.; Adams, S.; Rugo, H.S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Diéras, V.; Hegg, R. Im, S.A.; Shaw Wright, G.; Henschel, V.; Molinero, L.; Chui, S.Y.; Funke, R.; Husain, A.; Winer, E.P.; Loi, S.; Emens, L.A. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med., 2018, 379(22), 2108-2121.
[http://dx.doi.org/10.1056/NEJMoa1809615] [PMID: 30345906]
[98]
Yu, Y.; Cui, J. Present and future of cancer immunotherapy: A tumor microenvironmental perspective. Oncol. Lett.,, 2018, 16(4), 4105-4113.
[http://dx.doi.org/10.3892/ol.2018.9219] [PMID: 30214551]

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