Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Apigenin-mediated Alterations in Viability and Senescence of SW480 Colorectal Cancer Cells Persist in The Presence of L-thyroxine

Author(s): Bagheri Zohreh, Varedi Masoumeh*, Naghibalhossaini Fakhraddin and Gholam H.R. Omrani

Volume 19, Issue 12, 2019

Page: [1535 - 1542] Pages: 8

DOI: 10.2174/1871520619666190704102708

Price: $65

Abstract

Introduction: Deregulation of Thyroid Hormones (THs) system in Colorectal Cancer (CRC) suggests that these hormones may play roles in CRC pathogenesis. Flavonoids are polyphenolic compounds, which possess potent antitumor activities and interfere, albeit some of them, with all aspects of THs physiology. Whether the antitumor actions of flavonoids are affected by THs is unknown. Therefore, we investigated the effects of apigenin (Api), a well-known flavone, on some tumorigenic properties of SW480 CRC cells in the presence and absence of L-thyroxine (T4).

Methods: Cell viability was assessed by MTT assay. Flow cytometry and DNA electrophoresis were used to evaluate cell death. Cell senescence was examined by in situ detection of β-galactosidase activity. Protein expression was assessed by antibody array technique.

Results: While T4 had minimal effects, Api reduced cell growth and senescence by induction of apoptosis. Expression of anti-apoptotic and pro-apoptotic proteins were differentially affected by Api and T4. Survivin, HSP60 and HTRA were the most expressed proteins by the cells. Almost all Api-induced effects persisted in the presence of T4.

Conclusion: These data suggest that Api may inhibit CRC cell growth and progression through induction of apoptosis rather than cell necrosis or senescence. In addition, they suggest that T4 has minimal effects on CRC cell growth, and is not able to antagonize the anti-growth effects of Api. Regardless of the treatments, cells expressed high levels of survivin, HSP60 and HTRA, indicating that these proteins may play central roles in SW480 CRC cell immortality.

Keywords: Colorectal cancer, flavonoids, apigenin, thyroid hormones, apoptosis, cell senescence.

Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence 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]
[2]
Boikos, S.A.; Helman, L.J.; Stratakis, C.A. Pediatric and Wildtype GIST Clinic at the National Institutes of Health. Thyroid hormone inactivation in gastrointestinal stromal tumors. N. Engl. J. Med., 2014, 371(1), 85-86.
[PMID: 24988575]
[3]
Kester, M.H.; Kuiper, G.G.; Versteeg, R.; Visser, T.J. Regulation of type III iodothyronine deiodinase expression in human cell lines. Endocrinology, 2006, 147(12), 5845-5854.
[http://dx.doi.org/10.1210/en.2006-0590] [PMID: 16935842]
[4]
Pinto, M.; Soares, P.; Ribatti, D. Thyroid hormone as a regulator of tumor induced angiogenesis. Cancer Lett., 2011, 301(2), 119-126.
[http://dx.doi.org/10.1016/j.canlet.2010.11.011] [PMID: 21183275]
[5]
Sirakov, M.; Plateroti, M. The thyroid hormones and their nuclear receptors in the gut: from developmental biology to cancer. Biochim. Biophys. Acta, 2011, 1812(8), 938-946.
[http://dx.doi.org/10.1016/j.bbadis.2010.12.020] [PMID: 21194566]
[6]
Ishizuya-Oka, A.; Shi, Y.B. Molecular mechanisms for thyroid hormone-induced remodeling in the amphibian digestive tract: A model for studying organ regeneration. Dev. Growth Differ., 2005, 47(9), 601-607.
[http://dx.doi.org/10.1111/j.1440-169X.2005.00833.x] [PMID: 16316405]
[7]
Matosin-Matekalo, M.; Mesonero, J.E.; Laroche, T.J.; Lacasa, M.; Brot-Laroche, E. Glucose and thyroid hormone co-regulate the expression of the intestinal fructose transporter GLUT5. Biochem. J., 1999, 339(Pt 2), 233-239.
[http://dx.doi.org/10.1042/bj3390233] [PMID: 10191252]
[8]
Jumarie, C.; Malo, C. Alkaline phosphatase and peptidase activities in Caco-2 cells: Differential response to triiodothyronine. In Vitro Cell. Dev. Biol. Anim., 1994, 30A(11), 753-760.
[http://dx.doi.org/10.1007/BF02631298] [PMID: 7881629]
[9]
Dentice, M.; Luongo, C.; Ambrosio, R.; Sibilio, A.; Casillo, A.; Iaccarino, A.; Troncone, G.; Fenzi, G.; Larsen, P.R.; Salvatore, D. β-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. Gastroenterology, 2012, 143(4), 1037-1047.
[http://dx.doi.org/10.1053/j.gastro.2012.06.042] [PMID: 22771508]
[10]
Huang, S.A.; Fish, S.A.; Dorfman, D.M.; Salvatore, D.; Kozakewich, H.P.; Mandel, S.J.; Larsen, P.R.A.A. 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J. Clin. Endocrinol. Metab., 2002, 87(10), 4457-4461.
[http://dx.doi.org/10.1210/jc.2002-020627] [PMID: 12364418]
[11]
Huang, S.A.; Tu, H.M.; Harney, J.W.; Venihaki, M.; Butte, A.J.; Kozakewich, H.P.; Fishman, S.J.; Larsen, P.R. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N. Engl. J. Med., 2000, 343(3), 185-189.
[http://dx.doi.org/10.1056/NEJM200007203430305] [PMID: 10900278]
[12]
Dentice, M.; Luongo, C.; Huang, S.; Ambrosio, R.; Elefante, A.; Mirebeau-Prunier, D.; Zavacki, A.M.; Fenzi, G.; Grachtchouk, M.; Hutchin, M.; Dlugosz, A.A.; Bianco, A.C.; Missero, C.; Larsen, P.R.; Salvatore, D. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc. Natl. Acad. Sci. USA, 2007, 104(36), 14466-14471.
[http://dx.doi.org/10.1073/pnas.0706754104] [PMID: 17720805]
[13]
Goodman, A.D.; Hoekstra, S.J.; Marsh, P.S. Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res., 1980, 40(7), 2336-2342.
[PMID: 6770997]
[14]
Ko, A.H.; Wang, F.; Holly, E.A. Pancreatic cancer and medical history in a population-based case-control study in the San Francisco Bay Area, California. Cancer Causes Control, 2007, 18(8), 809-819.
[http://dx.doi.org/10.1007/s10552-007-9024-6] [PMID: 17632765]
[15]
Lin, H.Y.; Tang, H.Y.; Shih, A.; Keating, T.; Cao, G.; Davis, P.J.; Davis, F.B. Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic. Steroids, 2007, 72(2), 180-187.
[http://dx.doi.org/10.1016/j.steroids.2006.11.014] [PMID: 17174366]
[16]
Lee, Y.S.; Chin, Y.T.; Shih, Y.J.; Nana, A.W.; Chen, Y.R.; Wu, H.C.; Yang, Y.S.H.; Lin, H.Y.; Davis, P.J. Thyroid hormone promotes β-Catenin activation and cell proliferation in colorectal cancer. Horm. Cancer, 2018, 9(3), 156-165.
[http://dx.doi.org/10.1007/s12672-018-0324-y] [PMID: 29380230]
[17]
García-Silva, S.; Aranda, A. The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol. Cell. Biol., 2004, 24(17), 7514-7523.
[http://dx.doi.org/10.1128/MCB.24.17.7514-7523.2004] [PMID: 15314161]
[18]
Mackey, S. Promoting lifestyle modification for cancer prevention. J. Am. Diet. Assoc., 2004, 104(10), 1568-1569.
[http://dx.doi.org/10.1016/j.jada.2004.08.015] [PMID: 15389415]
[19]
Bravo, L. Polyphenols: Chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev., 1998, 56(11), 317-333.
[http://dx.doi.org/10.1111/j.1753-4887.1998.tb01670.x] [PMID: 9838798]
[20]
Block, G.; Patterson, B.; Subar, A. Fruit, vegetables, and cancer prevention: A review of the epidemiological evidence. Nutr. Cancer, 1992, 18(1), 1-29.
[http://dx.doi.org/10.1080/01635589209514201] [PMID: 1408943]
[21]
Menezes, J.C.; Orlikova, B.; Morceau, F.; Diederich, M. Natural and synthetic flavonoids: Structure-activity relationship and chemotherapeutic potential for the treatment of leukemia. Crit. Rev. Food Sci. Nutr., 2016, 56(Suppl. 1), S4-S28.
[http://dx.doi.org/10.1080/10408398.2015.1074532] [PMID: 26463658]
[22]
Ravishankar, D.; Rajora, A.K.; Greco, F.; Osborn, H.M. Flavonoids as prospective compounds for anti-cancer therapy. Int. J. Biochem. Cell Biol., 2013, 45(12), 2821-2831.
[http://dx.doi.org/10.1016/j.biocel.2013.10.004] [PMID: 24128857]
[23]
Zhu, Y.; Mao, Y.; Chen, H.; Lin, Y.; Hu, Z.; Wu, J.; Xu, X.; Xu, X.; Qin, J.; Xie, L. Apigenin promotes apoptosis, inhibits invasion and induces cell cycle arrest of T24 human bladder cancer cells. Cancer Cell Int., 2013, 13(1), 54.
[http://dx.doi.org/10.1186/1475-2867-13-54] [PMID: 23724790]
[24]
Wang, W.; Heideman, L.; Chung, C.S.; Pelling, J.C.; Koehler, K.J.; Birt, D.F. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog., 2000, 28(2), 102-110.
[http://dx.doi.org/10.1002/1098-2744(200006)28:2<102:AID-MC6>3.0.CO;2-2] [PMID: 10900467]
[25]
Lee, Y.; Sung, B.; Kang, Y.J.; Kim, D.H.; Jang, J.Y.; Hwang, S.Y.; Kim, M.; Lim, H.S.; Yoon, J.H.; Chung, H.Y.; Kim, N.D. Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Int. J. Oncol., 2014, 44(5), 1599-1606.
[http://dx.doi.org/10.3892/ijo.2014.2339] [PMID: 24626522]
[26]
Wang, W.; VanAlstyne, P.C.; Irons, K.A.; Chen, S.; Stewart, J.W.; Birt, D.F. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr. Cancer, 2004, 48(1), 106-114.
[http://dx.doi.org/10.1207/s15327914nc4801_14] [PMID: 15203384]
[27]
Moudgal, N.R.; Raghupathy, E.; Sarma, P.S. Studies on goitrogenic agents in food. III. Goitrogenic action of some glycosides isolated from edible nuts. J. Nutr., 1958, 66(2), 291-303.
[http://dx.doi.org/10.1093/jn/66.2.291] [PMID: 13599069]
[28]
de Souza Dos Santos, M.C.; Gonçalves, C.F.; Vaisman, M.; Ferreira, A.C.; de Carvalho, D.P. Impact of flavonoids on thyroid function. Food Chem. Toxicol., 2011, 49(10), 2495-2502.
[http://dx.doi.org/10.1016/j.fct.2011.06.074] [PMID: 21745527]
[29]
Gaitan, E.; Lindsay, R.H.; Reichert, R.D.; Ingbar, S.H.; Cooksey, R.C.; Legan, J.; Meydrech, E.F.; Hill, J.; Kubota, K. Antithyroid and goitrogenic effects of millet: Role of C-glycosylflavones. J. Clin. Endocrinol. Metab., 1989, 68(4), 707-714.
[http://dx.doi.org/10.1210/jcem-68-4-707] [PMID: 2921306]
[30]
Sartelet, H.; Serghat, S.; Lobstein, A.; Ingenbleek, Y.; Anton, R.; Petitfrère, E.; Aguie-Aguie, G.; Martiny, L.; Haye, B. Flavonoids extracted from fonio millet (Digitaria exilis) reveal potent antithyroid properties. Nutrition, 1996, 12(2), 100-106.
[http://dx.doi.org/10.1016/0899-9007(96)90707-8] [PMID: 8724380]
[31]
Divi, R.L.; Doerge, D.R. Inhibition of thyroid peroxidase by dietary flavonoids. Chem. Res. Toxicol., 1996, 9(1), 16-23.
[http://dx.doi.org/10.1021/tx950076m] [PMID: 8924586]
[32]
Divi, R.L.; Chang, H.C.; Doerge, D.R. Anti-thyroid isoflavones from soybean: Isolation, characterization, and mechanisms of action. Biochem. Pharmacol., 1997, 54(10), 1087-1096.
[http://dx.doi.org/10.1016/S0006-2952(97)00301-8] [PMID: 9464451]
[33]
Ferreira, A.C.; Rosenthal, D.; Carvalho, D.P. Thyroid peroxidase inhibition by Kalanchoe brasiliensis aqueous extract. Food Chem. Toxicol., 2000, 38(5), 417-421.
[http://dx.doi.org/10.1016/S0278-6915(00)00017-X] [PMID: 10762727]
[34]
Ferreira, A.C.; Neto, J.C.; da Silva, A.C.; Kuster, R.M.; Carvalho, D.P. Inhibition of thyroid peroxidase by Myrcia uniflora flavonoids. Chem. Res. Toxicol., 2006, 19(3), 351-355.
[http://dx.doi.org/10.1021/tx0501684] [PMID: 16544938]
[35]
Ferreira, A.C.; Lisboa, P.C.; Oliveira, K.J.; Lima, L.P.; Barros, I.A.; Carvalho, D.P. Inhibition of thyroid type 1 deiodinase activity by flavonoids. Food Chem. Toxicol., 2002, 40(7), 913-917.
[http://dx.doi.org/10.1016/S0278-6915(02)00064-9] [PMID: 12065212]
[36]
Spanka, M.; Hesch, R.D.; Irmscher, K.; Köhrle, J. 5′-Deiodination in rat hepatocytes: Effects of specific flavonoid inhibitors. Endocrinology, 1990, 126(3), 1660-1667.
[http://dx.doi.org/10.1210/endo-126-3-1660] [PMID: 2307124]
[37]
da-Silva, W.S.; Harney, J.W.; Kim, B.W.; Li, J.; Bianco, S.D.; Crescenzi, A.; Christoffolete, M.A.; Huang, S.A.; Bianco, A.C. The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes, 2007, 56(3), 767-776.
[http://dx.doi.org/10.2337/db06-1488] [PMID: 17327447]
[38]
Chandra, A.K.; De, N. Goitrogenic/antithyroidal potential of green tea extract in relation to catechin in rats. Food Chem. Toxicol., 2010, 48(8-9), 2304-2311.
[http://dx.doi.org/10.1016/j.fct.2010.05.064] [PMID: 20561943]
[39]
Auf’mkolk, M.; Koehrle, J.; Hesch, R.D.; Cody, V. Inhibition of rat liver iodothyronine deiodinase. Interaction of aurones with the iodothyronine ligand-binding site. J. Biol. Chem., 1986, 261(25), 11623-11630.
[PMID: 3488991]
[40]
Tatar, M.; Bagheri, Z.; Varedi, M.; Naghibalhossaini, F. Blackberry extract inhibits telomerase activity in human colorectal cancer cells. Nutr. Cancer, 2019, 71(3), 461-471.
[PMID: 30372130]
[41]
Matassov, D.; Kagan, T.; Leblanc, J.; Sikorska, M.; Zakeri, Z. Measurement of apoptosis by DNA fragmentation. Methods Mol. Biol., 2004, 282, 1-17.
[PMID: 15105553]
[42]
Wang, B.; Zhao, X.H. Apigenin induces both intrinsic and extrinsic pathways of apoptosis in human colon carcinoma HCT-116 cells. Oncol. Rep., 2017, 37(2), 1132-1140.
[http://dx.doi.org/10.3892/or.2016.5303] [PMID: 27959417]
[43]
Lefort, E.C.; Blay, J. Apigenin and its impact on gastrointestinal cancers. Mol. Nutr. Food Res., 2013, 57(1), 126-144.
[http://dx.doi.org/10.1002/mnfr.201200424] [PMID: 23197449]
[44]
Lin, H.Y.; Tang, H.Y.; Keating, T.; Wu, Y.H.; Shih, A.; Hammond, D.; Sun, M.; Hercbergs, A.; Davis, F.B.; Davis, P.J. Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: Both actions are integrin and ERK mediated. Carcinogenesis, 2008, 29(1), 62-69.
[http://dx.doi.org/10.1093/carcin/bgm239] [PMID: 17984113]
[45]
Chin, Y.T.; Wei, P.L.; Ho, Y.; Nana, A.W.; Changou, C.A.; Chen, Y.R.; Yang, Y.S.; Hsieh, M.T.; Hercbergs, A.; Davis, P.J.; Shih, Y.J.; Lin, H.Y. Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr. Relat. Cancer, 2018, 25(5), 533-545.
[http://dx.doi.org/10.1530/ERC-17-0376] [PMID: 29555649]
[46]
Takashina, M.; Inoue, S.; Tomihara, K.; Tomita, K.; Hattori, K.; Zhao, Q.L.; Suzuki, T.; Noguchi, M.; Ohashi, W.; Hattori, Y. Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells. Int. J. Oncol., 2017, 50(3), 787-797.
[http://dx.doi.org/10.3892/ijo.2017.3859] [PMID: 28197625]
[47]
LaCasse, E.C.; Baird, S.; Korneluk, R.G.; MacKenzie, A.E. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene, 1998, 17(25), 3247-3259.
[http://dx.doi.org/10.1038/sj.onc.1202569] [PMID: 9916987]
[48]
Kawasaki, H.; Altieri, D.C.; Lu, C.D.; Toyoda, M.; Tenjo, T.; Tanigawa, N. Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res., 1998, 58(22), 5071-5074.
[PMID: 9823313]
[49]
Ryan, B.M.; O’Donovan, N.; Duffy, M.J. Survivin: A new target for anti-cancer therapy. Cancer Treat. Rev., 2009, 35(7), 553-562.
[http://dx.doi.org/10.1016/j.ctrv.2009.05.003] [PMID: 19559538]
[50]
Wang, X.; Chen, M.; Zhou, J.; Zhang, X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (Review). Int. J. Oncol., 2014, 45(1), 18-30.
[http://dx.doi.org/10.3892/ijo.2014.2399] [PMID: 24789222]
[51]
Zhang, W.L.; Gao, X.Q.; Han, J.X.; Wang, G.Q.; Yue, L.T. Expressions of Heat Shock Protein (HSP) family HSP 60, 70 and 90alpha in colorectal cancer tissues and their correlations to pathohistological characteristics. Chin. J. Cancer, 2009, 28(6), 612-618.
[PMID: 19635199]
[52]
Spiess, C.; Beil, A.; Ehrmann, M. A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell, 1999, 97(3), 339-347.
[http://dx.doi.org/10.1016/S0092-8674(00)80743-6] [PMID: 10319814]
[53]
Lipinska, B.; Zylicz, M.; Georgopoulos, C. The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J. Bacteriol., 1990, 172(4), 1791-1797.
[http://dx.doi.org/10.1128/jb.172.4.1791-1797.1990] [PMID: 2180903]
[54]
Kim, D.Y.; Kim, K.K. Structure and function of HtrA family proteins, the key players in protein quality control. J. Biochem. Mol. Biol., 2005, 38(3), 266-274.
[PMID: 15943900]
[55]
Di Micco, R.; Fumagalli, M.; Cicalese, A.; Piccinin, S.; Gasparini, P.; Luise, C.; Schurra, C.; Garre’, M.; Nuciforo, P.G.; Bensimon, A.; Maestro, R.; Pelicci, P.G.; d’Adda di Fagagna, F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 2006, 444(7119), 638-642.
[http://dx.doi.org/10.1038/nature05327] [PMID: 17136094]
[56]
Zambrano, A.; García-Carpizo, V.; Gallardo, M.E.; Villamuera, R.; Gómez-Ferrería, M.A.; Pascual, A.; Buisine, N.; Sachs, L.M.; Garesse, R.; Aranda, A. The thyroid hormone receptor β induces DNA damage and premature senescence. J. Cell Biol., 2014, 204(1), 129-146.
[http://dx.doi.org/10.1083/jcb.201305084] [PMID: 24395638]
[57]
Ferbeyre, G.; de Stanchina, E.; Lin, A.W.; Querido, E.; McCurrach, M.E.; Hannon, G.J.; Lowe, S.W. Oncogenic Ras and p53 cooperate to induce cellular senescence. Mol. Cell. Biol., 2002, 22(10), 3497-3508.
[http://dx.doi.org/10.1128/MCB.22.10.3497-3508.2002] [PMID: 11971980]
[58]
Coppé, J.P.; Patil, C.K.; Rodier, F.; Sun, Y.; Muñoz, D.P.; Goldstein, J.; Nelson, P.S.; Desprez, P.Y.; Campisi, J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol., 2008, 6(12), 2853-2868.
[http://dx.doi.org/10.1371/journal.pbio.0060301] [PMID: 19053174]
[59]
Banerjee, K.; Mandal, M. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol., 2015, 5, 153-162.
[http://dx.doi.org/10.1016/j.redox.2015.04.009] [PMID: 25965143]

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